Restoring the infected powerhouse: Mitochondrial quality control in sepsis

Abstract

Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria fulfil dual roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function but also influence inflammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual impact, compromising both immune system efficiency and the metabolic stability of end organs. Dysfunctional mitochondria contribute to the development of a hyperinflammatory state and loss of cellular homeostasis, resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mitochondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria. However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mitochondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facilitate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis, specifically mitophagy, and the optimal timing for intervention remain poorly understood. This review emphasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects associated with solely the induction of mitochondrial biogenesis.

Full text

Redox Biology 68 (2023) 102968
Available online 23 November 2023
2213-2317/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Restoring the infected powerhouse: Mitochondrial quality control in sepsis
F.M. Lira Chavez
a
,
1
,
*
, L.P. Gartzke
a
,
1
,
**
, F.E. van Beuningen
a
, S.E. Wink
a
, R.H. Henning
a
,
G. Krenning
a
,
b
, H.R. Bouma
a
,
c
a
Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, 9713, GZ Groningen, the Netherlands
b
Sulfateq B.V, Admiraal de Ruyterlaan 5, 9726, GN Groningen, the Netherlands
c
Department of Internal Medicine, University Medical Centre Groningen, University of Groningen, 9713, GZ Groningen, the Netherlands
ARTICLE INFO
Keywords:
Sepsis
Mitochondrial quality control
Mitochondrial biogenesis
Mitochondrial dynamics
Mitophagy
ABSTRACT
Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is
complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that
culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria full dual
roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function
but also inuence inammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual
impact, compromising both immune system efciency and the metabolic stability of end organs. Dysfunctional
mitochondria contribute to the development of a hyperinammatory state and loss of cellular homeostasis,
resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and
consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of
mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss
mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as
therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mito-
chondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that
results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria.
However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mito-
chondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the
disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of
mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facili-
tate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post
sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may
provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis,
specically mitophagy, and the optimal timing for intervention remain poorly understood. This review em-
phasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects
associated with solely the induction of mitochondrial biogenesis.
1. Introduction
Sepsis is a systemic host response to an infection that is characterized
by organ failure and is among the leading causes of death worldwide [5,
6]. The World Health Organization (WHO) declared sepsis a global
health priority in 2017 and adopted a resolution to improve the pre-
vention, diagnosis, and management of sepsis. Despite the extensive
research being conducted, the pathophysiology of sepsis remains only
partially understood [6]. Sepsis survival has increased over the last
decades, but mortality remains around 20% [7,8]. Currently, the most
important outcome predictor remains time-to-antibiotics, in case sepsis
patients present with hypotension [9] as therapeutic options directed at
the molecular cause of sepsis induced organ dysfunction are lacking. The
mainstay of treatment therefore remains to be antimicrobial therapy and
* Corresponding author.
** Corresponding author.
E-mail address: f.m.lira.chavez@umcg.nl (F.M. Lira Chavez).
1
The authors with equal contribution are F. M. Lira Chavez and L. P. Gartzke.
Contents lists available at ScienceDirect
Redox Biology
journal homepage: www.elsevier.com/locate/redox
https://doi.org/10.1016/j.redox.2023.102968
Received 12 October 2023; Received in revised form 7 November 2023; Accepted 15 November 2023

Redox Biology 68 (2023) 102968
2
supportive care [6,10]. There is a long-established recognition that the
host response, rather than the pathogen itself, is responsible for much of
the tissue damage observed in sepsis [6,8,11]. In particular, the hyper-
inammatory response that can occur in sepsis can lead to widespread
tissue damage and organ failure [6,8,12], exposing sepsis survivors
increased all-cause mortality risk as well as functional and cognitive
impairments [13,14]. Additionally, mitochondrial dysfunction is
considered to play a key role in the induction of organ damage and
failure in sepsis [15].
Mitochondrial quality control (mtQC) is the process by which
mitochondria maintain their ability to respirate and regulate their
multiple effector functions. Mitochondrial DNA (mtDNA) is replicated
and transcribed in the mitochondrial matrix. Damage to mtDNA can lead
to mitochondrial dysfunction and disease [16–18]. Besides energy pro-
duction, mitochondria are involved in cellular processes such as calcium
homeostasis, the generation of reactive oxygen species (ROS), and the
initiation of cell death [19]. In sepsis, mitochondria play a crucial role in
maintenance of endothelial cell homeostasis [20,21], where dysfunction
can lead to both micro- and macrovascular complications. Mitochondria
further play a critical role in the immune system in sepsis, as they are
central to both the energy metabolism of immune cells and the regula-
tion of inammation through ROS generation and inammasome as-
sembly [22].
Sepsis leads to mitochondrial electron transport chain (ETC) complex
dysfunction, particularly of complexes I, III and IV [1]. Dysfunctional
mitochondria can contribute to the development of a (hyper)inam-
matory state [23,24] by increasing ROS production during infection in
response to pathogen-associated molecular patterns (PAMPs) [25],
damage-associated molecular patterns (DAMPs) [26], and
pro-inammatory cytokines released by leukocytes as part of the host
immune response [27]. In response to pro-inammatory cytokines
during sepsis, skeletal muscle cells produce and release nitric oxide
(NO). In septic patients, excessive NO production links to an increased
requirement for vasopressor drugs to maintain blood pressure, and
ndings show a positive correlation between tissue nitrite/nitrate con-
centrations and disease severity, as well as between complex I activity
and both reduced ATP and glutathione concentrations. Conversely,
vasopressor requirement is inversely correlated with both complex I
activity and ATP concentrations, and between nitrite/nitrate levels and
both complex I activity and reduced glutathione concentrations. These
ndings underpin organ failure resulting from bioenergetic malfunction
[28]. Mitochondrial dysfunction in sepsis leads to increased oxidative
stress, which is responsible for most of the cell damage observed
[29–31]. The oxidative stress can lead to damage to the mitochondrial
membrane, which results in increased mitochondrial permeability and
leakage of mitochondrial DNA into the circulation, where it may act as a
DAMP, thereby perpetuating the systemic inammatory response [32].
Finally, in mice and human broblasts mitochondrial dysfunction in-
duces cellular senescence and accelerates aging [33], which may very
well account for the increased morbidity and mortality observed in
sepsis patients [5,9,14]. This observation further supports the correla-
tion between mitochondrial dysfunction, inammation, and clinical
outcomes in sepsis.
To summarise, in addition to promoting immune system activation,
mitochondrial dysfunction also contributes to the organ failure in sepsis
and poor clinical outcome. Based on the current knowledge, mito-
chondria have a dual role during infections: while they play a crucial
role in generating cellular energy and regulating the innate immune
response, damage to mitochondria leads to dysfunctional mitochondria
with impaired ATP production and excessive ROS formation contrib-
uting to inammation and organ damage. Yet, how mitochondrial
quality control mechanisms inuence the course of sepsis is currently
unclear. Thus, this review discusses the effects of modulating mito-
chondrial quality control mechanisms and their association with sepsis
outcomes.
2. Relevance of patent mitochondria in sepsis
2.1. Mitochondrial dysfunction and immune cell activation
Having established mitochondria as central organelles in the context
of sepsis and its outcomes, we now delve deeper into the necessity of
mitigating mitochondrial damage and the ramications of dysfunctional
mitochondria for disease progression in sepsis. Our focus will be
directed towards understanding mitochondria as catalysts for inam-
mation, contributors to vascular complications, and mediators of cell
death and end-organ dysfunction in sepsis (Fig. 1).
Mitochondria play an important role in the innate immune system.
One way that mitochondria act as immune defence effectors is by acti-
vating the inammasome [40]. Mitochondria from both immune and
non-immune cells increase ROS production during infection in response
to both pathogen-associated molecular patterns (PAMPs) [25] and
DAMPs [26]. ROS are important signalling molecules that contribute to
pathogen (particularly bacterial) clearance, while excessive ROS gen-
eration can lead to tissue damage [41]. PAMPs from the invading
pathogens, as well as DAMPs from injured tissues, can stimulate the
NLRP3 inammasome [34,35]. Mitochondrial DNA (mtDNA) is a central
DAMP in the propagation of the immune response and associated
damage [17,42]. When mtDNA is released from damaged or stressed
cells, it can enter neighbouring cells and activate the inammasome by
binding to the protein NOD-like receptor family, pyrin
domain-containing 3 (NLRP3) [43,44]. NLRP3 is responsible for initi-
ating the production of pro-inammatory cytokines such as
interleukin-1 beta (IL-1β) and IL-18 [36,37]. In turn, pro-inammatory
cytokines released as part of the host response contribute to the sys-
temic inammatory response seen in sepsis, causing tissue damage and
organ dysfunction [27,45].
In sepsis, mitochondria play a dual role in both aiding pathogen
clearance and causing tissue damage. Mitochondrial components, like
DNA and ROS, can activate the inammasome, in turn increasing levels
of pro-inammatory cytokines. This activation, exacerbated by signals
from both damaged cells and bacterial elements, intensies inamma-
tion, resulting in further tissue harm and organ dysfunction. Grasping
the mitochondrial role in the immune response offers insights into sepsis
pathophysiology.
2.2. Metabolic reprogramming contributes to (micro)vascular and organ
dysfunction in sepsis
Metabolic reprogramming refers to the adaptive shifts cells undergo
in their energy production and consumption pathways, optimizing their
function in response to specic environmental cues or challenges [46].
Metabolic reprogramming, which is essential for mounting an adequate
immune response, particularly inuences neutrophils and macrophages
by leveraging mitochondria for citrate production, fatty acid synthesis,
and ATP generation, thereby facilitating rapid proliferation and effector
function. This metabolic shift towards aerobic glycolysis is known as the
Warburg effect [38,39]. Neutrophils and macrophages require relatively
large amounts of ATP to carry out their effector functions and are among
the rst cells to undergo metabolic reprogramming in sepsis [47].
Although aerobic glycolysis is less efcient than oxidative phosphory-
lation for energy production, the Warburg effect allows rapid generation
of metabolic intermediates and ATP required to allow fast proliferation
of leukocytes [38,48]. Next to generating ATP, glycolysis also leads to
the production of lactate and pyruvate, of which the latter normally
enters the Krebs cycle for oxidative phosphorylation. However, both
lactate and pyruvate can act as radical scavengers during infection,
thereby precluding the toxic effects of free radicals, but also leading to a
depletion of lactate and pyruvate to fuel the Krebs cycle [49]. Eventu-
ally, almost all bodily cells undergo metabolic reprogramming to cope
with the energy depletion and with the potential shortage of oxygen in
case of shock associated with sepsis [48].
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Redox Biology 68 (2023) 102968
3
Mitochondrial dysfunction in endothelial cells contribute to the
pathophysiology of sepsis. Under healthy conditions, these mitochon-
dria play a crucial role in cell signalling, primarily attributed to their
ability to generate reactive oxygen species (ROS) and maintain calcium
homeostasis, which is essential for proper endothelial cell function [50].
Impaired vascular contractility, increased vascular permeability, and
reduced nitric oxide (NO) bioavailability due to the activation of
endothelial cells by inammatory cytokines collectively culminate in
what is generally referred to as endothelial dysfunction [50]. Further-
more, dysfunctional mitochondria within endothelial cells contribute to
oxidative stress and damage to crucial cellular components, including
lipids, proteins, and DNA, further compromising endothelial cell func-
tion [51].
In the context of sepsis, microvascular dysfunction is characterized
by impaired regulation of blood ow, heightened vascular permeability,
and disrupted cell-cell interactions [52]. Mitochondrial dysfunction in
endothelial cells plays a signicant role in the development of these
abnormalities by disrupting normal cellular signalling pathways, pro-
moting inammation, and inducing oxidative stress [52]. Impaired
endothelial cell function and compromised vascular integrity stand as
critical contributors to the pathophysiology of sepsis, driving its pro-
gression and associated complications.
The kidney is among the most vulnerable organs in the sepsis
population and sepsis induced acute kidney injury (sepsis-AKI) is
strongly associated with poor outcomes [53,54]. Accordingly, preven-
tion of sepsis-AKI and recovery of function are on the forefront of sepsis
research. Mitochondrial metabolic reprogramming signicantly affects
the kidney, with mitochondrial dysfunction and altered metabolism
being recognized as key driving forces in the aetiology of sepsis-AKI
[55]. Upon mitochondrial failure, (an)aerobic glycolysis takes over
ATP production as evidenced in kidney tubular epithelial cells (i.e.
Warburg effect), but this process also leads to the production of lactate
[56]. However, lactate can lead to (intracellular) acidication, swelling
of cells and thereby compromise microvascular function and perfusion
of the organ [57]. Inhibiting glycolysis partially restores mitochondrial
membrane potential and decreases ROS production, resulting in reduced
mitochondrial and kidney injury [56]. Preservation of mitochondrial
function with the chromanol-based compound SUL-138 in lipopolysac-
charide (LPS) challenged endothelial cells and sepsis in mice induced by
caecal ligation and puncture (CLP) improved mitochondrial complex I
and complex IV activity and limited mitochondrial ROS generation,
resulting in lower systemic inammation and dampening of acute kid-
ney injury [58].
To sum up, (an)aerobic glycolysis increases ROS production, while
changes in metabolism during the acute inammatory response modify
mitochondrial bioenergetics and lead to mitochondrial injury, which in
Fig. 1. Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) interact with cell surface receptors, including Toll-like
receptors (TLRs) and other pattern recognition receptors (PRRs), initiating the cascade of mitochondrial dysfunction and inammation in sepsis [25,26]. Mito-
chondria within the cell emit reactive oxygen species (ROS) molecules, symbolizing oxidative stress which in turn triggers the formation of the inammasome, key
components such as NOD-like receptors (NLRs), apoptosis-associated speck-like protein (ASC), and procaspase 1 come together, marking the initiation of the in-
ammatory response [34,35]. Cytokines, such as IL-1β and IL-18, are secreted from the cell and result in mitochondrial damage [36,37]. Fragments of mitochondrial
DNA released from the damaged mitochondria act as DAMPs. A feedback loop is formed perpetuating the cycle of inammation and cellular response. Further
mitochondrial damage results in the upregulation of the glycolytic pathway (Warburg effect) [38,39].
F.M. Lira Chavez et al.

Redox Biology 68 (2023) 102968
4
turn result in organ dysfunction. Particularly, endothelial ROS produc-
tion impairs NO signalling, which impairs endothelial (organ)function,
particularly vasomotor control and barrier function of the endothelium,
which can be restored through supporting mitochondrial complexes I
and IV function.
2.3. Mitochondrially-mediated mechanisms of cell death in sepsis
Mitochondria play a signicant role in cell death regulation, where
cell damage and cell death occur even in non-severe cases of sepsis.
Changes in mitochondrial membrane potential and assembly of the
mitochondrial permeability transition pore (MPT) can drive necrosis
[59] and apoptosis [60]. Sepsis associated apoptosis, triggered by the
release of cytochrome c from stressed or damaged mitochondria, is
observed in lymphocytes and epithelial cells [61]. In severe sepsis,
lymphocyte apoptotic cell death plays a crucial role in the development
of shock and multi-organ dysfunction syndrome (MODS), contributing
to the impaired immune response frequently encountered in the
immune-paralysis phase of sepsis [62]. Likewise, diaphragm mito-
chondria of septic mice of exhibit increased proton leak and down-
regulation of superoxide dismutase 2 (SOD2), potentially resulting in
cell death from apoptosis and ferroptosis mediated by ROS [63].
Iron-dependent cell injury is of particular relevance among the
pathways leading to cell injury because it plays a critical role in pro-
moting a cascade of events that exacerbate tissue damage in sepsis.
Sepsis increases iron-dependent cell injury and death through lipid
peroxidation, specically ferroptosis. Intracellular iron levels increase
due to upregulated expression of transferrin receptor 1 (TFR1) and
divalent metal transporter 1 (DMT1) activity [64], while macrophages
release iron from damaged erythrocytes after phagocytosis [65]. The
accumulation of ROS and expansion of the iron-pool promote ferrop-
tosis, a necrotic form of cell death. Ferroptosis releases DAMPs from cells
[66], perpetuating inammation. Inammasome formation and caspase
activation, induced by inammation, cause gasdermin cleavage [67].
Cleaved gasdermin forms membrane pores that promote cytolysis
leading to pyroptosis, another necrotic form of cell death [68].
Yes-associated protein 1 (YAP1) acts as a ferroptosis suppressor by
regulating the intracellular labile iron pool. YAP1 knockout sepsis mice
contract more severe acute lung injury and show lowered ferroptosis
defence as compared to wildtype animals, as demonstrated by the
downregulation of GPx4, TH1, and SCL7A11, and concurrent increases
in promotors of lipid peroxidation, including SFXN1 and NCOA4. In
LPS-stimulated lung epithelial cells, YAP1 deciency was associated
with increased labile iron pool and mitochondrial dysfunction, leading
to ferroptosis. Accordingly, YAP1 overexpression prevented the degra-
dation of ferric iron to ferrous iron and conferred protection from
mitochondrial dysfunction [69]. In summary, iron-dependent cell injury
represents a key pathway that amplies tissue damage and
inammation.
In sepsis, mitochondria act as central regulators of cell fate, driving
both cell survival and death through mechanisms intimately linked with
their function and structure. Disturbances in mitochondrial function,
such as the release of cytochrome c and changes in membrane potential,
not only initiate cell death but can perpetuate further cellular demise
and activate other forms of regulated cell death.
3. Mitochondrial quality control
Assessing the severity of sepsis and predicting its clinical course is
challenging in clinical practice. Nonetheless, numerous biomarkers have
emerged as potential indicators to assess disease severity. Notably,
specic biomarkers associated with the immunosuppressive phase of
sepsis, such as anti-inammatory cytokines and changes in the cell
surface markers of monocytes and lymphocytes, have been investigated.
Monocytes in sepsis play essential roles in phagocytosis and antigen
presentation but can also trigger dangerous inammation through
excessive cytokine production [70]. Monocyte distribution width
(MDW) is a valuable marker for early sepsis detection, especially in the
emergency department. In regard to lymphocytes, sepsis can result in
severe lymphopenia resulting from increased apoptosis, reduced T-cell
proliferation, and cytokine production [71–73]. Specically, lympho-
cyte subsets, especially CD4 T lymphocytes, assessed upon hospital
admission in patients subsequently developing sepsis, have emerged as
promising biomarkers for identifying those at a heightened risk of an
unfavourable outcome [74]. In sepsis, neutrophils are stimulated but
struggle to migrate effectively to infection sites, contributing to the
condition and even organ failure [75]. Neutrophil CD64 has been
identied as a promising biomarker for outcome prediction among pa-
tients with an infection. High nCD64 expression during early sepsis
might be associated with a better prognosis [76,77].
It is important to know there is no one biomarker that can accurately
predict the outcome of sepsis, but by employing a multi-marker panel
comprising both pro- and anti-inammatory biomarkers, it may be
possible to identify patients who will progress towards severe sepsis at
an early stage, before signicant organ dysfunction ensues [78]. Various
mitochondrial parameters, including mitochondrial membrane poten-
tial and oxidative stress, have been suggested as potential biomarkers for
assessing clinical recovery and the response to oxygen therapy in sepsis
[15]. Improvement in mitochondrial parameters during treatment may
indicate a positive outcome in sepsis patients. In patients with
sepsis-associated acute kidney injury (sepsis-AKI), disturbances in
mitochondrial quality control are evident. These patients often exhibit a
reduction in mitochondrial mass, increased oxidative stress, and
decreased expression of mitochondrial biogenesis markers, all of which
suggest a decrease in mitochondrial quality control [91]. As a result of
these mechanisms, septic patients have shown changes in mitochondrial
morphology, such as fragmentation and swelling, prompting the
development of drugs targeting mitochondria to enhance sepsis survival
[79]. Given the role of mitochondria as drivers of inammation and
organ failure, we propose that measuring mitochondrial function and
markers of mitochondrial quality control could serve as future guides for
assessing both the severity, progression and treatment effect of sepsis.
Mitochondria form highly dynamic intracellular networks that
execute quality control mechanisms to regulate their population
numbers and network structure through processes including mitochon-
drial biogenesis (mitogenesis), ssion/fusion (mitochondrial dynamics),
and autophagic degradation (mitophagy). Mitochondrial homeostasis is
ensured through the delicate balance of these quality control processes
[80,81]. Mitochondria respond to stress by changing their mass, shape
and interconnectivity. Changes in mitochondrial mass reect alterations
between mitochondrial biogenesis and mitophagy, whereas changes in
ssion/fusion dynamics are reected by the interconnectivity of the
mitochondrial reticulum [30]. Additionally, ssion and mitophagy play
a crucial role in pruning dysfunctional parts of the mitochondrial
network.
The relationship between sepsis and mitochondrial dysfunction has
been the subject of extensive research, which has identied mitochon-
drial damage as a major contributor to sepsis morbidity and mortality
[1,30,82] (see also references below). A prominent example is that
mitochondrial membrane depolarization in thrombocytes correlates
with clinical disease severity in patients with sepsis during the pro-
gression of the disease [83]. Since septic patients may already present
with mitochondrial dysfunction, it will not be possible to fully prevent it
in sepsis. Thus, efforts should be expanded to promote the recovery of
mitochondrial function. As such, we propose that the rst phase of
mitochondrial sepsis management comprises the limitation of further
mitochondrial damaged by preventing ROS generating, while the second
phase should aim to induce mitochondrial quality control (mtQC)
mechanisms to recover mitochondria integrity and function. Based on
the above, it seems to be biologically plausible that such an approach
would combine promoting mitophagy for removal of damaged and
dysfunctional mitochondria and stimulating biogenesis to increase the
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Redox Biology 68 (2023) 102968
5
pool of functional mitochondria for bioenergetics.
3.1. Mitogenesis and biogenesis
Though sometimes used interchangeably, mitochondrial biogenesis
and mitogenesis denote distinct but interrelated processes. Within the
overarching process of mitochondrial biogenesis, mitogenesis refers to
the initiation of mitochondrial division or ssion, facilitated by the
dynamin-related protein 1 (DRP1). It entails the replication of mito-
chondrial DNA and the proliferation of existing mitochondria, a process
comparable to mitosis. In contrast, mitochondrial biogenesis delineates
a broader concept, emphasizing the enhancement – rather than mere
preservation – of mitochondrial mass by producing new mitochondria
[84]. This comprehensive process is underpinned by the synthesis of
mitochondrial DNA and the assembly of mitochondrial structures.
Central to this is the TFAM-PCG1a-NRF1/2 pathway (Fig. 2). For uni-
formity throughout this review, we employ the term "mitochondrial
biogenesis" when referring to this specic pathway. This approach un-
derscores the emphasis on proteins localized at mitochondria yet are
encoded in the nuclear genome regulated by transcription factors
including the PGC1 family, Nrf1 and Nrf2, and on nuclear-encoded
mitochondrial transcription factors such as TFAM, TFB1M, and TFB2M
[85].
3.2. TFAM-PGC1
α
-NRF1/2-pathway controls both biogenesis and
mitogenesis
The core transcription initiation complex to reproduce mtDNA is a
specialized assembly of proteins, involving mitochondrial RNA poly-
merase (POLRMT), transcription factor A (TFAM), and transcription
factor B2M (TFB2M), that binds to specic DNA sequences, facilitating
the commencement of transcription by positioning and guiding the RNA
polymerase to initiate RNA synthesis from the DNA template [89].
Central to the process of mitochondrial biogenesis is the TFAM-
PGC1
α
-NRF1/2-pathway, a pivotal regulator of the mitochondrial life
cycle and its response to stress. TFAM, in particular, is vital in the
generation of new mitochondria. TFAM achieves this by binding to
distinct mitochondrial DNA sequences, promoting their transcription
and replication [80]. It oversees mitochondrial DNA replication and
transcription, while the mitochondrial transcription specicity factor
(TFBM) assists in bringing RNA polymerase to the mitochondrial DNA
promoter, thereby forming the core transcription initiation complex for
human mitochondria [90]. Together, their upregulation fosters
increased mitochondrial gene expression and protein production.
Interestingly, even though overall TFAM expression is heightened in
peripheral blood mononuclear cells (PBMCs) of sepsis patients
compared to controls, a marked decrease in its level inside mitochondria
suggests an impediment in mitochondrial TFAM uptake. The reduced
intramitochondrial TFAM, observed in sepsis patients, leads to a corre-
sponding decrease in mitochondrial DNA copy numbers, mtND1
expression, and overall cellular ATP content [88]. This was further
evidenced by a similar behaviour of LPS-stimulated PBMCs from healthy
individuals [88]. Moreover, the interplay between TFAM and TFB2M
within the core transcription initiation complex appears compromised in
septic patients. The skewed ratio of intra-over extramitochondrial
TFAM, brought about by increased extramitochondrial levels of TFAM -
but reduced intramitochondrial levels of TFAM - might explain the
sepsis paradox of increased TFAM expression, yet absence of bio-
energetic recovery due to the diminished mitochondrial TFAM presence.
Post-mortem sepsis studies have shown a downregulation in genes tied
to mtQC, including those related to TFAM (biogenesis), which likely
contributes to the aforementioned discrepancy [91].
PGC-1 proteins, particularly PGC-1
α
, are pivotal in mtDNA replica-
tion, with emerging research positioning PGC-1
α
as the central regulator
of mitochondrial biogenesis [81]. Furthermore, PGC-1
α
is recognized as
the cornerstone in overseeing the mitochondrial lifecycle and response
to oxidative stress [92]. Notably, there is noticeable mitochondrial
swelling and dysfunction within tubular epithelial cells during sepsis-
AKI. This is further compounded by a selective suppression in the
expression of oxidative phosphorylation genes and a corresponding
decline in mitochondrial biogenesis, mainly attributed to diminished
PGC-1
α
levels. Interestingly, elevated levels of the pro-inammatory
cytokine TNF-
α
correlate with decreased PGC-1
α
abundance and
reduced oxygen consumption — a sign of mitochondrial failure.
Fig. 2. The relationship between sepsis and mitochondrial biogenesis. During the initial stages of sepsis, there is a notable downregulation of mitochondrial
biogenesis. This reduction is primarily driven by elevated levels of the cytokine TNF
α
, which leads to decreased levels of PGC-1
α
[86]. As sepsis progresses to its later
stages, mitochondrial dysfunction becomes increasingly evident. In response to this dysfunction, a defensive cellular response is initiated to counteract oxidative
stress and prevent cell death. STAT3 enhances the mitochondrial membrane potential, thus improving ATP production efciency, which is crucial for cellular energy
supply. In an effort to maintain energy production, cells increase fatty acid oxidation. This is achieved, in part, by inhibiting the degradation of CPT1, a key enzyme
involved in fatty acid transport into mitochondria [87] Additionally, the increased expression of Nrf1 and Nrf2, along with TFAM, suggests an upregulated response
to cope with dysfunctional mitochondria [2]. However, a notable challenge emerges in the form of impaired TFAM translocation into the mitochondria [88]. This
impairment potentially explains the contradictory results observed regarding mitochondrial biogenesis in sepsis.
F.M. Lira Chavez et al.

Redox Biology 68 (2023) 102968
6
However, augmenting PGC-1
α
levels can counter this trend. The
essential role of PGC-1
α
in preserving renal function is further under-
scored by experiments in tubule-specic PGC-1
α
knockout mice, that
compared to wildtype mice show pronounced increases AKI severity
upon LPS injection, as evidenced by heightened serum creatine and urea
nitrogen levels [86]. Additionally, in mice PGC-1
α
is a critical player in
restoring renal recovery by enhancing nicotinamide adenine biosyn-
thesis and thereby correcting ischemia-induced energy shortages and
restoring renal function [93]. Hence, PGC-1
α
emerges as a vital mech-
anism in safeguarding kidney function during sepsis, primarily by
averting mitochondrial failure through induction of mitochondrial
biogenesis.
Nuclear factor erythroid 2-related factor 2 (Nrf2) stands as a central
transcription factor, governing the expression of various antioxidant and
cytoprotective genes to counter oxidative stress, inammation, and
toxins. In mice, activation of Nrf2 through Heme oxygenase-1 (HO-1)
sparks mitochondrial biogenesis, effectively safeguarding them from
fatal Staphylococcus aureus (S. aureus) sepsis [94]. Protection can be
further enhanced by carbon monoxide (CO) inhalation that leads to
upregulation of Nrf2-dependent genes, amplifying mitochondrial
biogenesis, curtailing inammation, and thus enhancing sepsis survival.
The protective effect of CO, however, diminishes when both Nrf2 and
Akt1 are knocked down, emphasizing their combined role in mito-
chondrial biogenesis [94]. Mirroring this, sub-lethal S. aureus sepsis in
mice instigates renal mitochondrial injury but also ignites renal mtDNA
repair and mitochondrial biogenesis [95]. During sepsis-induced renal
inammation, there is a notable increase in mtDNA repair and mito-
chondrial biogenesis, as evidenced by heightened 8-oxoguanine DNA
glycosylase (OGG1) activity. This upsurge in OGG1, along with
augmented expression of Nrf1, Nrf2, and TFAM, suggests a defensive
response aimed at counteracting oxidative stress and cell death. More-
over, the rise in renal mitochondrial mass and the central role of Nrf2 in
driving mitochondrial biogenesis imply an inherent healing mechanism
following systemic bacterial invasion [2]. The toxic effects of LPS on
myocardium can be effectively countered by the induction of the Nrf2
and Nrf1 pathways. Songorine, an active C20-diterpene alkaloid, le-
verages this protective mechanism by bolstering cardiac function
through Nrf2 induction [2]. Upon exposure to LPS, cardiomyocytes
typically experience mitochondrial ROS generation and a calcium surge,
but these effects are mitigated by songorine. Moreover, songorine en-
hances antioxidant defences, boosts mitochondrial gene expression
associated with fatty acid β-oxidation and electron transport, and in-
vigorates the Nrf1 and TFAM pathways in an Nrf2-dependent fashion.
However, in Nrf2-decient mice exposed to LPS, the cardioprotective
efcacy of songorine diminishes, underscoring its modulatory action
through the Nrf2 and Nrf1 pathways. In conclusion, ensuring efcient
transport of these transcription factors into mitochondria is paramount,
as their impaired uptake might exacerbate conditions, highlighting the
importance of maintaining these protein levels within mitochondria.
LPS treatment elevates mitochondrial biogenesis in rats, with PGC-
1
α
and TFAM being upregulated, leading to a 20% surge in mitochon-
drial mass within 24 h [96]. This contradicts human ndings as one of
the characteristics of sepsis-induced mitochondrial dysfunction is
impaired translocation of TFAM [97] despite cytosolic upregulation
[88]. Additionally, a recent review concluded that sepsis is associated
with decreased intramitochondrial TFAM levels. Phosphorylation of
human TFAM impairs DNA binding and consequently to initiate tran-
scription [98], however we are not aware of literature directly demon-
strating increased TFAM phosphorylation in human sepsis. Intriguingly,
the above introduced augmented biogenesis in rats is not reected in
improved mitochondrial function [96]. Mitochondrial respiration
showed vulnerabilities: complex I activity was curtailed by 30% at 6 and
24 h post-LPS treatment, and complex II function similarly dipped at 24
h after LPS challenge. Alongside this functional reduction, mitochon-
drial ultrastructure manifested various anomalies, including internal
vesicles, disrupted cristae, and swelling. Building on this observation,
similar ndings have been noted in diaphragms of septic CLP mice.
Despite the benecial upregulation of mitochondrial biogenesis markers
in other contexts, the septic diaphragms tell a more disheartening story.
A signicant decline in the quantity and quality of mitochondria is
evident, which might be attributed to the suppressed expression of
PGC-1
α
[63]. This septic state also witnesses a downregulation of res-
piratory chain complexes, most notably complex III and IV, leading to
subdued oxygen consumption tied to ADP phosphorylation. The broader
picture suggests that mitochondria show a compounded impairment
during sepsis: downregulated mitochondrial biogenesis and
oxidative-stress-induced damage, culminating in diminished mitochon-
drial mass.
Early mitochondrial biogenesis appears paramount to survive sepsis
induced critical illness. Patients who survived showed a higher muscle
ATP levels and reduced phosphocreatine to ATP ratio and exhibited
(early) induction of mitochondrial biogenesis and antioxidant defence
[99]. The induction of mitochondrial biogenesis and antioxidant
defence seems to counterbalance mitochondrial protein depletion, thus
preserving mitochondrial functionality and energy balance. However,
there was still depletion of respiratory protein subunits and their tran-
scripts (PPARGC1A, NRF1, and TFAM). Notably, only survivors man-
ifested increased levels of the mitochondrial oxidative stress protein
manganese superoxide dismutase (MnSOD) and the mitochondrial
biogenesis associated transcript PPARGC1A. The contrast is stark with
non-survivors, whose reduced mtQC response might increase their
vulnerability to mitochondrial damage, possibly hampering cellular
energy functionality and thwarting recovery to a normal state [100].
3.3. Sirtuins and STAT3: integrated modulators of mitochondrial
biogenesis and cellular energy metabolism
Sirtuins and STAT3 are key modulators of mitochondrial dynamics
and cellular bioenergetics, whose modulation could improve outcomes
for sepsis patients, given the protective role of early mitochondrial
biogenesis in critical illness. Silent information regulator 2-related his-
tone deacetylases, i.e. sirtuins (SIRTs), are a 7 member protein family
serving as critical nexuses in cellular activities, encompassing aging,
inammation, and bioenergetics, especially in the realm of mitochon-
drial biogenesis. Two if its members have been implicated in sepsis,
specically SIRT1 and SIRT3. SIRT1 mandates the presence of nicotin-
amide adenine dinucleotide (NAD) for the deacetylation of its target
substrates [101,102]. The cellular redox balance of NAD+and NADH,
intrinsically connected to catabolic metabolism, casts SIRT1 as a meta-
bolic sensor that coherently aligns metabolic imbalances with tran-
scriptional responses. This understanding is strengthened by SIRT1’s
interaction and NAD +-dependent deacetylation of PGC-1
α
[103].
SIRT1, primarily recognized as a nuclear/cytosolic protein [104–106],
exerts a pivotal role in sepsis by guiding inammation and mitochon-
drial dynamics through two main avenues. First, it activates PGC-1
α
via
deacetylation, enabling PGC-1
α
to ally with the mitochondrial tran-
scription factor A (TFAM). This partnership is fundamental for directing
mitochondrial DNA replication and transcription [104,105]. Secondly,
SIRT1 enhances the expression of the strictly mitochondrial SIRT3 via
the RELB pathway, an NF-κB transcription factor family member [107].
As sepsis takes hold, there is a profound alteration in monocyte behav-
iour and a shift in their mitochondrial fuel preference, both driven by the
SIRT1-RELB-SIRT3 axis [108]. Therefore, current research underscores
the dominant inuence of SIRTs on mitochondrial biogenesis via PGC-1
α
[109].
Signal transducer and activator of transcription 3 (STAT3) is a
multifaceted protein that is implicated across a spectrum of cellular
activities, from proliferation and survival to energy metabolism, all
while regulating mitochondrial calcium levels. Upon exposure to LPS,
STAT3 augments the mitochondrial membrane potential, thus
enhancing ATP production efciency. Moreover, STAT3 bolsters mito-
chondrial biogenesis and heightens fatty acid oxidation by inhibiting the
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Redox Biology 68 (2023) 102968
7
degradation of carnitine palmitoyl transferase 1a (CPT1a), an enzyme
responsible for facilitating the transport of long-chain fatty acids into the
mitochondria, through its interaction with ubiquitin-specic peptidase
50 (USP50). However, in absence of USP50, STAT3 levels rise and
CPT1a remains active and abundant within in the cell, leading to
improved fatty acid oxidation, and as a result reduced lipid damage. The
overexpression of STAT3 in mitochondria, however, augments the
severity of LPS-induced sepsis as reected in enhanced NF-κB activity
[87]. Thus, STAT3 function appears to be dualistic, acting as both a
protective agent by enhancing ATP production and a damaging agent by
the escalation of sepsis when overexpressed in mitochondria.
In summary, mitochondrial biogenesis is central to sepsis progres-
sion. Despite the valuable perspectives gained from clinical observations
of the involvement of mtQC in sepsis, there is a notable gap in experi-
mental evidence from human-based interventions. Biomarkers reecting
mitochondrial biogenesis and function may adequately and timely
assess sepsis severity and predict the clinical outcome. It is crucial,
however, to acknowledge the existing gaps and limitations in the current
body of research that support this hypothesis. Although some studies
have indicated that recovery from sepsis likely depends on early acti-
vation of mitochondrial biogenesis and a balanced biogenesis response,
as excessive biogenesis can be counterproductive in causing structural
anomalies and reduced mitochondrial functionality, it requires further
validation through extensive research. However, harnessing the poten-
tial of the interconnected pathways driving mitochondrial biogenesis
might offer novel therapeutic avenues for sepsis.
3.4. Pharmacological compounds for enhancing biogenesis in sepsis
recovery
Pharmacological activation of mitochondrial biogenesis can be
achieved with a large range of compounds (Fig. 3). While the effects of
many of these compounds in the context of sepsis have yet to be thor-
oughly investigated, the fundamental pathways responsible for stimu-
lating biogenesis are well-established in the literature. The proteasome
inhibitor and anticancer drug bortezomib can prevent degradation of
unbound (DNA-free) TFAM [98]. In a murine macrophage sepsis model
bortezomib decreased pro-inammatory cytokine levels and increased
survival after LPS challenge, in keeping bortezomib treatment in rats
prior to CLP increased seven day survival and decreased lung inam-
mation [110]. Given TFAM’s central role in biogenesis, prevention of its
degradation through bortezomib may hold therapeutic potential. The
drug bezabrate activates a group of receptors known as peroxisome
proliferator-activated receptors (PPARs) and is commonly used to treat
dyslipidaemia [111]. In mice, bezabrate stimulates the expression of
the key regulator PGC-1
α
in the heart and skeletal muscles [112]. It also
increases respiratory capacity and restores oxidative phosphorylation
function in broblasts with complex III or complex deciencies from
patients with inherited genetic mitochondrial disorders [113]. In a
murine model of Huntington’s disease, bezabrate improved mito-
chondrial numbers and function in brain and muscle tissue by bringing
PGC-1
α
levels back to normal. Thereby attenuating neuronal atrophy, i.
e. neurodegeneration, and preventing the conversion of oxidative to
glycolytic muscle bres. Finally, bezabrate protected against oxidative
damage substantiated amongst other by reduced DNA-damage and lipid
peroxidation [114].
Resveratrol is known for its ability to activate sirtuins, particularly
SIRT1, in mammals [115]. Resveratrol activates AMP-activated protein
kinase (AMPK), leading to increased cellular NAD +levels, which in
turn activates SIRT1 [116]. AMPK activation is considered a crucial
factor in the mechanism of action of resveratrol on SIRT1 and mito-
chondrial biogenesis. AMPK is activated through phosphorylation at
Thr172. This activation is inuenced by AMP and ADP binding,
reecting cellular energy status as indicated by AMP/ATP and ADP/ATP
ratios [117]. AMPK acts as a metabolic sensor that responds to changes
in cellular energy levels. The combined action of activated AMPK and
SIRT1 promotes mitochondrial biogenesis via PGC-1
α
activation [118].
Overall, resveratrol has demonstrated therapeutic potential in a wide
range of diseases, often attributed to its antioxidant or
anti-inammatory, however, its impact has not yet been extensively
Fig. 3. Resveratrol activates AMP-activated protein kinase (AMPK), leading to an increase in cellular NAD +levels, which subsequently activates SIRT1 [116]. This
dual activation of AMPK and SIRT1 together promotes mitochondrial biogenesis through the activation of PGC-1
α
[118]. Bezabrate, on the other hand, activates
peroxisome proliferator-activated receptors (PPARs) and enhances respiratory capacity while protecting against oxidative damage [112]. Pioglitazone, a PPARγ
agonist, stimulates PPAR and TFAM expression [122], mitigating the inammatory response by partially inhibiting NF-κB activation [123]. Additionally, bortezomib
prevents the degradation of unbound (DNA-free) TFAM [98], which is central to mitochondrial biogenesis, suggesting therapeutic potential in preserving
TFAM integrity.
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Redox Biology 68 (2023) 102968
8
studied in a sepsis model.
PPARγ agonists, such as pioglitazone [119], have garnered attention
for their potential to stimulate biogenesis in several neurodegenerative
diseases [120,121]. This research presents promising avenues for
addressing conditions characterised by inammatory brain symptoms.
Notably, in patients with type 2 diabetes, pioglitazone treatment has
demonstrated a signicant increase in both mitochondrial copy number
and the expression of genes related to mitochondrial biogenesis [122]
including peroxisome proliferator–activated receptor, PGC-1
α
and
TFAM. Furthermore, in the context of sepsis, pioglitazone mitigates the
inammatory response, by partially inhibiting NF-κB activation [123].
This effect was demonstrated in a CLP mouse model treated with pio-
glitazone. It is worth noting, however, the study did not explore its ef-
fects on mitochondrial function.
4. Mitophagy
On the one hand, mitochondria are instrumental in orchestrating an
immune response during sepsis, but on the other hand, they can inad-
vertently exacerbate harm. While mitochondrial dysfunction predomi-
nantly leads to an increase in ROS production at the expense of ATP
generation, inducing mitogenesis and mitochondrial biogenesis can
provide new therapeutic targets to reinstate cellular bioenergetic ho-
meostasis. However, with an understanding of the associated pitfalls,
our attention now pivots to the critical process of clearing damaged
mitochondria, called mitochondrial autophagy, or in short: mitophagy.
Autophagy and mitophagy are intertwined processes that degrade and
recycle cellular components in response to stress; while mitophagy tar-
gets dysfunctional mitochondria, autophagy addresses broader cellular
elements, reecting their shared mechanisms and roles in cellular health
[124]. As such, mitophagy is a selective form of autophagy, which
removes mitochondria as a response to various stimuli, such as nutrient
starvation, oxidative stress or programmed mitochondrial removal
[125]. As one of the mechanisms of mitochondrial quality control,
mitophagy balances mitochondrial ROS production by removing
dysfunctional mitochondria responsible for the overproduction of ROS.
Sepsis induces early autophagy, but leads to impaired autophagy in later
stages. Induction of autophagy by rapamycin reduced the severity of
tubular epithelial injury and preserved renal function after CLP in mice
[126].
There are different pathways that regulate mitophagy (Fig. 4),
however the best-studied is the pathway mediated by phosphatase and
tensin homolog (PTEN)-induced kinase PINK1 and E3-ubiquitin ligase
Parkin [127]. PINK1 accumulates at the OMM (outer mitochondrial
membrane) in response to mitochondrial injury, increased ROS, depo-
larization, or accumulation of misfolded proteins. The accumulated
PINK1 is then auto-phosphorylated, which in turn phosphorylates
ubiquitin to recruit Parkin from the cytosol to the mitochondrial mem-
brane [128]. Parkin, when recruited and activated, drives the ubiquiti-
nation of various mitochondrial inner proteins, which recruit and
activate more Parkin (through positive feedback). Phosphorylated Par-
kin delivers ubiquitinated mitochondria to autophagosomes, resulting in
removal of damaged mitochondria by mitophagy [129].
4.1. PINK1-parkin mediated mitophagy
Phosphatase and tensin homolog (PTEN)-induced kinase PINK1 and
E3-ubiquitin ligase Parkin [127] are important regulators of mitophagy,
with relevance to regulation of immune function and preserving organ
function in sepsis. PINK1 accumulates at the outer mitochondrial
membrane (OMM) in response to mitochondrial injury, increased ROS
levels, mitochondrial membrane depolarization, or accumulation of
misfolded proteins. The accumulated PINK1 is then
auto-phosphorylated, which in turn phosphorylates ubiquitin to recruit
Parkin from the cytosol to the mitochondrial membrane [128]. Parkin,
when recruited and activated, drives the ubiquitin-mediated autophagy
and mitophagy which recruits and activates more Parkin through a
positive feedback loop. Phosphorylated Parkin delivers ubiquitinated
mitochondria to autophagosomes, resulting in removal of damaged
mitochondria by mitophagy [129]. By this process, a reduction in PINK1
inhibits mitophagy, inadvertently elevating mitochondrial fragmenta-
tion through dynamin-related protein 1 (Drp1)-related mitochondrial
ssion, which, however, can be counteracted by parkin overexpression.
Hence, PINK1 primarily ensures protection by bolstering mitophagy and
curbing mitochondrial fragmentation [132].
Mitophagy is essential to maintain cellular homeostasis by preser-
ving mitochondrial function. Knock-out of PINK1 and parkin exacer-
bates AKI in septic mice, induced by either LPS or CLP. Additionally,
Fig. 4. The relationship between sepsis and PINK1-Parkin mediated mitophagy. In the early stages of sepsis, the induction of iNOS leads to the production of ROS
which subsequently initiates two critical processes: The activation of mitophagy, mediated by Nrf2, which orchestrates the induction of the PINK1-Parkin pathway.
And the stimulation of mitochondrial biogenesis [130]. In the later phases of sepsis, mitophagy becomes impaired. This impairment may be attributed to the cleavage
of Parkin by caspases activated by NLRP3 [131]. (For interpretation of the references to colour in this gure legend, the reader is referred to the Web version of
this article.)
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Redox Biology 68 (2023) 102968
9
knockdown of PINK1 and Parkin in renal proximal tubular cells (RPTC)
treated with LPS lowers the accumulation of the autophagy adaptor
optineurin, indicative of reduced autophagy in the cells. In line with
this, genetic silencing of optineurin reduces LPS-induced mitophagy.
These ndings demonstrate the importance of the PINK1-Parkin-
optineurin pathway in conferring protection from sepsis-AKI by induc-
tion of mitophagy [133]. In murine hepatocytes, LPS induces expression
of inducible nitric oxide synthase (iNOS) and subsequent production of
ROS. Subsequently, the iNOS-ROS signalling pathway triggers activa-
tion of mitophagy and mitochondrial biogenesis in hepatocytes via Nrf2,
which mediates the induction of PINK1 and Parkin, in response to
iNOS-ROS signalling [130].
In early murine sepsis-AKI mitophagy is elevated, but impaired in the
later phase, potentially due to the cleavage of the mitophagy promotor
Parkin via caspases activated by NLRP3: a damage response protein that
is part of the inammasome. Impaired mitophagy is associated with the
accumulation of damaged mitochondria, oxidative stress, and cell death.
Indeed, loss of mitophagy increased mitochondrial-associated apoptosis
increased over time during sepsis-AKI in mice. Therefore, promoting
mitophagy during sepsis-AKI may be a promising therapeutic strategy to
prevent apoptosis and attenuate AKI [131]. Sepsis-AKI can also be
attenuated via promoting Nrf2 nuclear translocation. The activation of
Nrf2 is an important adaptive response to cellular stress, as it allows cells
to upregulate the defence against oxidative stress and increases the
expression of genes involved in inammation, DNA repair, and auto-
phagy. The renal protective effects of mitophagy are further supported
by Gao et al. (2020) [3] who demonstrated that polydatin treatment
protects from sepsis-AKI through induction of Parkin-mediated
mitophagy. Treatment with polydatin prevented mitochondrial
dysfunction by reducing mitochondrial mass via upregulation of
mitophagy by activating SIRT1 and inhibiting the formation of the
NLRP3-inammasome, and partially precluded AKI in septic mice.
Additionally, the PINK1-Parkin-pathway seems to play an important
role in modulation sepsis-induced muscle atrophy. Accumulation of
dysfunctional, damaged mitochondria are considered crucial catalysts
for muscle catabolism. Parkin counteracts catabolism and its over-
expression prevented a decrease in the content of mitochondrial sub-
units of NADH dehydrogenase and cytochrome C oxidase, and
attenuated sepsis-induced muscle wasting in CLP-sepsis mice [134].
4.2. Non-PINK1–parkin-mediated mitophagy: Beclin-1 and MKK3
While the PINK1-Parkin pathway is the most well-known pathway
for mitophagy, there are several other pathways that can mediate this
process, each with their own unique regulatory mechanisms. Beclin-1,
also known as autophagy-related protein 6 (ATG6), is a protein that
plays a key regulatory role in autophagy and mitophagy [135].
Administration of the Beclin-1 peptide protects mitochondria associated
membranes (MAMs), specialized regions that govern interaction be-
tween endoplasmic reticulum (ER) and mitochondria, in LPS-stimulated
human cardiomyocytes, while loss of Beclin-1 has the opposite effect
[136]. Consistent with this work, upregulation of Beclin-1 promotes
autophagy and mitophagy and reduces the release mitochondrial
DAMPs, resulting in reduced inammation in LPS-stimulated mice
[137]. Mitophagy can also be regulated by the mitogen-activated pro-
tein kinase 3 (MKK3), a protein kinase that is involved in the regulation
of cellular responses to stress and inammation involving modulation of
mitochondrial biogenesis and mitophagy. Activation of MKK3 is
increased in peripheral blood mononuclear cells (PBMCs) from septic
patients compared with non-septic controls. Wildtype CLP mice sus-
tained higher inammatory cell inltration in the lungs, increased levels
of oxidative stress, whereas MKK3 knockout mice have lower levels of
mitochondrial injury, with increased mitochondrial biogenesis and
mitophagy, reduced lung injury and improved survival in sepsis [138].
The ndings suggest a critical role for MKK3-driven mitophagy in
maintaining pool of healthy mitochondria in sepsis with relevance to
preservation of organ function and survival.
In summary, mitophagy plays a crucial role in promoting benecial
outcomes as demonstrated in murine sepsis models by reducing oxida-
tive stress, maintaining mitochondrial function, and decreasing
inammation, brosis, and organ injury. The PINK1-parkin pathway is a
critical regulator of mitophagy, and overexpression of Parkin attenuates
sepsis-induced muscle wasting. Furthermore, treatment with rapamycin,
polydatin, and Beclin-1 peptide can enhance (mitochondrial) auto-
phagy, leading to improved outcomes in sepsis. Targeting (mitochon-
drial) autophagy seems a promising therapeutic strategy to lower
morbidity and mortality from sepsis. Further research is needed to better
understand the molecular mechanisms underlying mitophagy regulation
in sepsis and to develop targeted interventions that can enhance the
benecial effects.
4.3. Pharmacological options of mitophagy induction
Rapamycin (Sirolimus) is an immunosuppressant used to prevent
organ rejection in transplant recipients [139] and to treat certain
autoimmune diseases [140]. It suppresses T-lymphocyte activation and
proliferation through mammalian target of rapamycin (mTOR) inhibi-
tion. In experimental models of murine spinal cord [141] and rat cere-
bral ischemia [142], rapamycin showed promise in promoting
rapamycin signicantly boosted mitophagy by facilitating the trans-
location of p62 and Parkin to the mitochondria. Another investigation
revealed that rapamycin upregulated the expression of
mitophagy-promoting genes, such as PINK1 and PARKIN [143]. Addi-
tionally, a third study [144] highlighted how rapamycin effectively
rescued mitochondrial myopathy through the synchronized activation
of autophagy and the enhancement of lysosomal biogenesis. Further-
more, in a sepsis model induced by CLP in mice [145], pretreatment
with rapamycin has been associated with decreased inammation,
pyroptosis suppression, and reduced organ damage, ultimately
contributing to improved survival rates (Fig. 5).
Metformin, a widely prescribed drug for type 2 diabetes, is known for
its primary antidiabetic effects through the inhibition of mitochondrial
complex I activity, resulting in improved glycaemic control [146].
Recent research has unveiled its broader applicability in enhancing
mitochondrial function and promoting mitophagy. Studies involving
type 2 diabetes patients have demonstrated metformin’s ability to
reduce HbA1c levels, alleviate mitochondrial oxidative stress, and
upregulate mitophagy markers like PINK1 and Parkin as well as pre-
serving mitochondrial integrity [147]. Additionally, metformin en-
hances AMPK activation and mitochondrial function, reversing
pro-inammatory cytokine increases observed in diabetic patients
[148]. In the context of sepsis management, metformin’s antioxidant
and anti-inammatory properties are gaining attention, as it reduces
reactive oxygen species production, suppresses pro-inammatory cyto-
kines, modulates inammation-related transcription factors, and main-
tains mitochondrial membrane potential, all without evidence of lactic
acidosis at therapeutic doses in human diabetic PBMCs [148]. These
ndings highlight the potential repurposing of metformin for broader
clinical applications beyond diabetes management, particularly in sepsis
and associated organ failure, due to its multifaceted effects encom-
passing mitophagy stimulation, improved mitochondrial function, and
inammation attenuation.
NAD +precursors, such as nicotinamide riboside (NR), hold promise
as a therapeutic avenue. In human broblasts NR activates sirtuins and
promotes mitophagy, impacting cellular health and mitochondrial
function positively [149]. NAD +plays a crucial role in regulating NAD
+-dependent deacetylases [150–152], including SIRT1, SIRT3, and
SIRT6, all of which have been demonstrated to facilitate mitophagy by
deacetylating essential proteins in the process. These deacetylation
events involve key players like PINK1 and Parkin, and further under-
score the signicance of NAD+in governing mitophagy-related mech-
anisms across different SIRT proteins. NR treatment can decrease
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Redox Biology 68 (2023) 102968
10
mitochondrial content while maintaining quality, and elevated
NAD+/NADH ratios, along with SIRT1 activation, yield similar effects,
including decreased mitochondrial content, increased autophagy, and
mitochondrial fragmentation. In sepsis mouse models, NR administra-
tion prior to sepsis onset elevated NAD +levels, reducing oxidative
stress, inammation, and caspase-3 activity in lung and heart tissues,
improving pulmonary microvascular permeability and myocardial
function, and reducing mortality [153]. NR also suppressed plasma high
mobility group box-1 (HMGB1) levels, prevented ROS production and
apoptosis, and enhanced NAD +content, while inhibiting SIRT1 offset
these benets, emphasizing the importance of the NAD+/SIRT1 sig-
nalling pathway in NR-mediated protection. As NR is already a health
supplement, its potential to prevent organ injury in sepsis represents a
promising therapeutic strategy, highlighting its role in enhancing
cellular health and mitigating mitochondrial dysfunction through sir-
tuin activation and mitophagy promotion.
Melatonin, both endogenously produced by the pineal gland and
available as a supplement, has emerged as a promising therapeutic agent
with the dual capacity to promote mitophagy and provide protection
against mitochondrial dysfunction and oxidative stress [154]. The
relationship between melatonin and mitophagy is complex as some
studies suggest that melatonin enhances mitophagy, while others sug-
gest that it represses it. One study found that melatonin enhances
mitophagy in human mesenchymal stem cells under oxidative stress by
upregulating the expression of heat shock 70 kDa protein 1L (HSPLA)
[155]. However, another study suggests that melatonin may provide
benecial effects on mitochondrial function by repressing mitophagy
[156]. In a study involving septic newborns, melatonin’s antioxidant
properties were evaluated, revealing that melatonin treatment signi-
cantly reduced elevated levels of lipid peroxidation products, specif-
ically malondialdehyde (MDA) and 4-hydroxylalkenals (4-HDA),
commonly seen in septic infants compared to healthy controls [157].
This reduction in MDA and 4-HDA levels substantiates a mitigation of
oxidative stress. This underscores melatonin’s potential as an antioxi-
dant and protective agent against oxidative stress in sepsis, with impli-
cations for improving clinical outcomes and increasing survival rates
among septic patients, making it a promising therapeutic candidate for
conditions marked by mitochondrial dysfunction, oxidative damage,
and inammation, such as sepsis. Overall, the relationship between
melatonin and mitophagy is an area of active research, and more studies
are needed to fully understand the mechanisms involved.
Prohibitin 1 (PHB1) and prohibitin 2 (PHB2), collectively known as
prohibitins, are ubiquitously expressed proteins. PHB1 is an inner
mitochondrial membrane (IMM) protein that forms a heterodimeric
complex with PHB2. This complex stabilizes the structure of the mito-
chondrial membrane and regulates various mitochondrial functions,
including mitophagy [158,159]. PHB1 has been shown to induce
mitophagy in response to increased mitochondrial reactive oxygen
species (ROS) through binding to the mitophagy receptor Nix/Bnip3L,
independently of Parkin [159]. In the context of sepsis, the role of PHB1
becomes even more signicant. An analysis of samples from 348 sepsis
patients revealed an inverse correlation between PHB1 expression and
the severity of sepsis [160]. It plays a vital role in regulating NLRP3
inammasomes, reducing PHB1 levels increases cytoplasmic mtDNA
levels and intensies the activation of the NLRP3 inammasome. When
a mitophagy inhibitor is applied, it reverses the inammasome activa-
tion induced by PHB1 knockdown. The cardioprotective impact of PHB1
in sepsis is evident by its ability to promote survival and protect the
circulatory system [161]. Enhancing PHB1 levels, whether through
overexpression or recombinant human PHB1 treatment, boosts the
antioxidant and anti-inammatory response in HL-1 cardiomyocytes.
This protection extends to shielding the cells from mitochondrial
dysfunction and cytokine-induced toxicity. Notably, when recombinant
human PHB1 was administered, it mitigated inammation, revived
Fig. 5. Metformin enhances AMPK activation and mitochondrial function, reducing pro-inammatory cytokines and mitigating mitochondrial oxidative stress [148].
It also upregulates mitophagy markers like PINK1 and Parkin, preserving mitochondrial integrity [147]. NR regulates NAD +-dependent deacetylases, including
SIRT1, SIRT3, and SIRT6, which facilitate mitophagy by deacetylating key proteins like PINK1 and Parkin [150–152]. Rapamycin signicantly boosts mitophagy by
promoting the translocation of p62 and Parkin to mitochondria and increasing the expression of mitophagy-promoting genes, such as PINK1 and PARKIN [143].
Melatonin enhances mitophagy by elevating the expression of heat shock 70 kDa protein 1L (HSPLA) [155] and reduces lipid peroxidation products like malon-
dialdehyde (MDA) and 4-hydroxylalkenals (4-HDA) [157]. (For interpretation of the references to colour in this gure legend, the reader is referred to the Web
version of this article.)
F.M. Lira Chavez et al.

Redox Biology 68 (2023) 102968
11
cardiac contractility, and restored ATP production in mice subjected to a
lipopolysaccharide challenge. In conclusion, the multifaceted role of
prohibitin 1 (PHB1) in maintaining mitochondrial integrity, regulating
inammasome activity, and its cardioprotective effects during sepsis
underscores its potential as a valuable target for therapeutic in-
terventions in severe inammatory disorders (Table 1).
4.4. Mitophagy vs biogenesis
While biogenesis and mitophagy have opposing functions, they are
counterparts of the same coin and are closely interlinked with one
another. Despite their opposing actions, both play essential roles in
protecting against organ damage and death during sepsis.
Mitophagy and mitochondrial biogenesis collaboratively balance
cellular energy production and oxidative stress control. For instance, in
THP-1 cells following LPS exposure [162], mitophagy curtails oxidative
stress by clearing dysfunctional mitochondria, while concurrent upre-
gulation of mitochondrial biogenesis ensures sustained energy provi-
sion. Together, they orchestrate a cellular defence against the adverse
effects of unregulated inammation during sepsis [162]. Interestingly,
while being opposite processes, both mitophagy and mitochondrial
biogenesis are increased in survival and recovery of sepsis. HO-1 is an
inducible enzyme that can be upregulated in response to various
stressors, including inammation, oxidative stress, and hypoxia [163].
Its upregulation is a protective response aimed at reducing oxidative
stress, inammation, and cellular damage. Induction of HO-1 by hemin
improved mitochondrial function by decreasing lipid peroxidation,
increasing mitochondrial biogenesis and mitophagy, and decreasing
ssion-related protein in CLP mice. Further, hemin treatment decreased
proinammatory cytokine levels in liver, organ damage and death of
septic mice. The benecial action of hemin in sepsis has been attributed
to the downregulation of TLR4 expression as, similar to hemin, treat-
ment with a TLR4 antagonist attenuated sepsis-induced mortality, in-
ammatory response, and mitochondrial dysfunction [163]. In line with
mitochondria-protective effects mediated by HO-1 induction, Shi et al.
(2019) [164] demonstrated that septic lung injury in rats can be atten-
uated by the induction of HO-1 through the PI3K/Akt pathway resulting
in increased mitochondrial quality control mechanisms, evidenced by
enhanced mitochondrial ssion/fusion, mitochondrial biogenesis,
mitophagy and a lower rate of apoptosis. It was accompanied by less
lung injury and a higher survival rate. LY294002, a PI3K inhibitor, or
knockdown of PI3K suppressed Akt phosphorylation and attenuated
induction of HO-1, thereby reversing the benecial effects evoked by
hemin pre-treatment. Together, these results suggest that HO-1 activa-
tion, through the PI3K/Akt pathway plays a critical role in protecting
the lung from oxidative injury in sepsis by regulating mitochondrial
quality control and may be a therapeutic target for preventing
sepsis-related lung injury.
Mitochondrial quality control mechanisms play a vital role in
maintaining mitochondrial function. Amidst the ongoing scientic
discourse surrounding the importance of these mechanisms, we offer an
alternative perspective: the key lies in the timing of the interventions
promoting mtQC in sepsis seem key and should be the focus of further
research is this area. Manfredini et al. (2019) [165] demonstrated
mitochondrial dysfunction is associated with long-term cognitive
impairment in rat sepsis. Sepsis was induced both acutely (24 h) and in
the long term (10 days. in adult Wistar rats using CLP. A week later, they
were treated with activators for biogenesis and autophagy or saline as a
control. Cognitive impacts were assessed through behavioural tests,
while brain mitochondrial functions were evaluated at various time
intervals post-sepsis. Treatment with rosiglitazone, which activates
mitochondrial biogenesis, or rapamycin and rilmenidine, which activate
autophagy, proved to be effective interventions. These treatments
improved brain ATP levels, enhanced oxygen consumption, and
importantly, ameliorated the long-term cognitive impairment observed
in sepsis survivors. Thus, mitophagy and mitochondrial biogenesis are
Table 1
Summary of pharmacological agents affecting mitochondrial quality control
mechanisms.
Compound Model Effect Reference
Biogenesis
Bortezomib HeLa cells Prevention of TFAM
degradation. Reduction
of inammatory
cytokines and
increased survival
Lu et al.
(2013)
Han et al.
(2015)
Bezabrate Mice Upregulation of PGC-
1
α
expression in
skeletal and heart
muscles
Hondares
et al. (2007)
Fibroblasts from
patients with genetic
mitochondrial
disorders
Restoration of PGC-1
α
levels, improved
mitochondrial copy
numbers. Restoration
of brain function and
protection from
oxidative damage by
lipid peroxidation
Sirvastava
et al. (2009)
Murine Huntington Johri et al.
(2012)
Resveratrol Saccharomyces
ervisiae
Activation of AMPK
resulting in increased
cellular NAD +
availability allowing
for SIRT1 activation
Howitz et al.
(2003)
HepG2 cells/LDL
receptor decient
mice
Zang et al.
(2006)
Pioglitazone DM II patients Upregulation of
biogenesis gene
expression (PGC-1
α
,
TFAM) and elevated
mitochondrial copy
numbers
Bogacka
et al. (2005)
CLP mice Inhibition of
inammatory response
via NF-κB activation
Kaplan et al.
(2014)
Rosiglitazone CLP rats Activation of
biogenesis. Improved
brain ATP availability,
oxygen consumption.
Ameliorated long term
cognitive impairment
Manfredini
et al. (2019)
Mitophagy
Rapamycin Transient middle
cerebral artery
occlusion rats
Promotion of
mitophagy via p62 and
Parkin mitochondrial
translocation
Li et al.
(2014)
U87MG cells Upregulation of
mitophagy gene
expression (PINK1,
Parkin)
Lenzi et al.
(2021)
Mice Rescue of
mitochondrial
myopathy via
autophagy and
lysosomal biogenesis
Civiletto
et al. (2018)
CLP mice Reduction of
inammation and
suppression of
pyroptosis limiting
organ damage
Wang et al.
(2019)
Rescue of cognitive
impairment via
enhanced autophagy
Liu et al.
(2017)
Rapamycin/
Rilmenidine
CLP rats Activation of
autophagy. Improved
brain ATP availability,
oxygen consumption.
Ameliorated long term
cognitive impairment
Manfredini
et al. (2019)
Metformin DM II patients Reduction of HbA1c
levels, mitochondrial
oxidative stress and
upregulation of PINK1,
Parkin
Bhansali
et al. (2020)
Enhanced AMPK
activation and reversed
Mara˜
n´
on
et al. (2022)
(continued on next page)
F.M. Lira Chavez et al.

Redox Biology 68 (2023) 102968
12
two functionally opposed mechanisms that are together essential to
maintain a healthy pool of mitochondria. This study underscores the
crucial role of mitochondrial dysfunction in long-term cognitive
impairment following sepsis. Moreover, it highlights the efcacy of
treatments that regulate mitochondrial function, especially during the
later stages of sepsis, as potential therapeutic strategies to mitigate
cognitive impairment in sepsis survivors. In line with these ndings, a
study conducted in a CLP mouse model demonstrated that early
administration of Rapamycin effectively rescued cognitive impairment
by boosting autophagy [166]. Taken together, it would be reasonable to
conclude that early administration of mitophagy-enhancing drugs dur-
ing sepsis may prove benecial by eliminating damaged and malfunc-
tioning mitochondria. Conversely, the administration of
biogenesis-enhancing drugs at a later stage could aid in replenishing
the necessary mitochondrial population, thus promoting healthy mito-
chondrial function.
5. Mitochondrial dynamics
Mitochondrial dynamics, specically ssion and fusion, involve
structural changes in existing mitochondria and plays a critical role in
regulating cellular bioenergetics. Mitochondria are dynamic organelles
which change morphology by undergoing coordinated cycles of ssion
or fusion and movement within the cell [167]. Mitochondrial ssion is
dened as the division of one mitochondrion into two (smaller)
daughter mitochondria, while conversely mitochondrial fusion refers to
the opposite process, the union of two mitochondria that results in one
larger mitochondrion [168]. Both ssion and fusion processes are
regulated by guanosine triphosphatases (GTPases), which are members
of the dynamin family, that divide and fuse the two lipid bilayers that
surround the mitochondria [169], the IMM and the OMM. The IMM
forms invaginations called cristae that surround the mitochondrial ma-
trix and contain most of the fully assembled complexes of the ETC and
ATP synthase, as well as substantial amounts of the soluble electron
transport protein cytochrome C [170], while the OMM surrounds the
IMM and the intermembrane space. The balance between mitochondrial
fusion and ssion plays a vital role in maintaining mitochondrial func-
tion, structure, and turnover [169]. Specically, ssion and fusion are
intricately linked to the regulation of mitophagy, as ssion usually tar-
gets dysfunctional mitochondria for mitophagy [171]. Conversely, the
fusion process is essential for the exchange of mitochondrial contents
and enabling repair of damaged mitochondria [172,173], a process
sometimes referred to as cross-complementation, which ultimately in-
uences mitochondrial biogenesis [174]. Hereby, ssion and fusion can
allow selective removal of damaged mitochondrial components through
redistribution followed by mitophagy [161]. Sepsis leads to a shift in the
ssion/fusion balance towards ssion [175], which could aid to clear
damage mitochondrial components via redistribution and mitophagy,
but can also contribute to increased oxidative stress and cell death in
sepsis (Fig. 6).
The adverse effects of mitochondrial ssion on organ dysfunction in
ICU-admitted sepsis patients are emphasized by the ndings of Huang
et al. (2021) [4]. MtQC-related biomarkers PGC-1
α
(promotor of mito-
chondrial biogenesis), ssion protein 1 (Fis1)(promotor of mitochon-
drial ssion), mitofusin2 (Mfn2)(promotor of mitochondrial fusion), and
Parkin (promotor of mitophagy) differ between healthy individuals and
through the stages of sepsis severity. In this population, the levels of
PGC-1
α
, Mfn2, and Parkin were lowest in healthy individuals, while the
levels of Fis1 were highest in the septic shock group – thus supporting a
shift from fusion to ssion in patients with sepsis as well. Lowered levels
of biomarkers for mitochondrial biogenesis and increased levels of
ssion biomarkers correlated with disease severity and progression, as
measured by the Sequential Organ Failure Assessment (SOFA) score.
This suggests that monitoring these biomarkers could help predict
outcome and guide treatment in septic patients. Induction of sepsis by
CLP in mice, leads to sepsis-AKI and disturbs ssion and fusion as
manifested by a relative increase in ssion over fusion [176]. Treatment
with procyanidin B2 (PBC2) shifted this balance back towards fusion,
reinforcing mitochondrial integrity. This not only curbed
mitochondrial-mediated apoptosis but also rectied impaired mitoph-
agy. The underlying mechanisms behind PBC2’s efcacy were multi-
faceted. One notable pathway involved the increased nuclear
translocation of the transcription factor Nrf2, which plays a role in both
the reduction of ROS accumulation and a decrease in mitochondrial
damage. Furthermore, Nrf2’s translocation to the nucleus enhanced
mitochondrial biogenesis, increasing the fusion-to-ssion ratio. More-
over, PBC2’s promotion of mitophagy effectively diminished the
build-up of damaged mitochondria, which subsequently decreased
associated apoptosis and cellular damage [176]. Organ dysfunction in
ICU-admitted sepsis patients are emphasized by the ndings of Huang
et al. (2021) [4]. MtQC-related biomarkers including PGC-1
α
Fis1,
Mfn2, and Parkin differ between healthy individuals and through the
stages of sepsis severity. In this population, the levels of PGC-1
α
, Mfn2,
and Parkin were lowest in healthy individuals, while the levels of Fis1
were highest in the septic shock group – highlighting the importance of
preventing mitochondrial scattering through ssion. Additionally, both
reduced biogenesis and increased ssion markers correlated with dis-
ease severity and progression (SOFA score), suggesting that monitoring
these biomarkers could help predict outcome and guide treatment in
Table 1 (continued )
Compound Model Effect Reference
pro inammatory
cytokine signalling
Nicotinamide
riboside (NR)
Human broblasts Promotion of
mitophagy and sirtuin
activation
Jang et al.
(2012)
LPS mice Elevation of NAD+,
reduced oxidative
stress, inammation
and caspase-3.
Hong et al.
(2018)
Melatonin Human
mesenchymal stem
cells
Enhanced mitophagy
via expression of
HSPLA
Yoon et al.
(2019)
Mouse granulose
cells
Repression of
mitophagy
Jiang et al.
(2021)
Septic newborns Reduction of lipid
peroxidation products
(MDA, 4-HAD)
Gitto et al.
(2001)
Prohibitin 1
(PHB1)
PHB1 decient
mice/Crohn’s
disease patients/
Mode-K cells
Induction of mitophagy
via Nix/Bnip3L (Parkin
independent)
Alula et al.
(2023)
Sepsis patient
material
Regulation of the
NLRP3 inammasome
and management of
cytoplasmic mtDNA
levels.
Chen et al.
(2023)
LPS treated HL-1
cardiomyocytes
Enhanced antioxidant
and anti-inammatory
responses
Mattox et al.
(2021)
LPS mice Mitigation of
inammation.
Restoration of ATP
production and cardiac
contractility.
Mattox et al.
(2021)
Fission/Fusion
Procynidin LPS mice Increased Nrf2 nuclear
translocation,
reduction in ROS,
increased fusion-to-
ssion ratio.
Liu et al.
(2020)
LPS treated lung
tissue and lung
epithelial cells
Limitation of
inammatory
response, oxidative
stress and apoptosis
Ning et al.
(2022)
Streptozotocin mice Promotion of SIRT3
dependent SOD2
deacetylation.
Liu et al.
(2017)
F.M. Lira Chavez et al.

Redox Biology 68 (2023) 102968
13
septic patients. Promoting fusion by melatonin confers protection
against acute lung injury [177] by reducing the inammatory response,
oxidative stress, and apoptosis in LPS-treated lung tissues and
LPS-treated lung epithelial cells. Melatonin also inhibited mitophagy
and restored fatty acid oxidation via the activation of the SIRT3/SOD2
signalling pathway. in LPS-treated lung epithelial cells in vitro and in
vivo. The interaction of melatonin with the melatonin receptor 1B
(MTNR1B) that plays a pivotal role in regulating glucose homeostasis
and insulin secretion, may explain the enhanced glucose uptake and
improved fatty acid oxidation [177]. The protective effects of melatonin
seem to be, at least in part, mediated through SIRT3. Inhibition of SIRT3
negated melatonin’s defensive capabilities against acute lung injury.
Melatonin not only boosted the activity and expression of SIRT3 but also
promoted the SIRT3-dependent deacetylation of superoxide dismutase 2
(SOD2), thereby increasing mitochondrial antioxidative capacity [178].
In essence, the alteration in mitochondrial dynamics, characterized
by increased ssion and decreased fusion events in sepsis, either leads to
or reects the accumulation of damaged mitochondria, oxidative stress,
and subsequent cell death. This aberrant ssion-to-fusion ratio can be
further exacerbated by impaired mitophagy, which allows the accu-
mulation of (ssioned, fragmented) damaged mitochondria. Promoting
clearance of damaged mitochondria by mitophagy and inducing mito-
chondrial fusion could reveal to be a potential therapeutic strategy to
attenuate organ dysfunction and improve outcomes in sepsis.
5.1. Future perspectives
Whether or not mitochondrial biogenesis, mitophagy, ssion/fusion
or all three mechanisms are key to improve sepsis outcomes, therapies
should ascertain not to increase the amount of circulating mtDNA as
elevated mtDNA in the circulation acts as a DAMP and induces remote
inammation. Higher levels of circulating mtDNA are associated with
systemic inammation, organ dysfunction [12] and long-term mortality
[179]. On the other hand, intact mitochondrial biogenesis seems crucial
as lowered circulatory mtDNA levels are associated with frailty and
all-cause mortality in the general population [180]. Age is inversely
associated with mtDNA copy number, with a higher mtDNA copy
number in women relative to men. Potentially, this observation may in
part account for better outcomes of female sepsis patients as observed by
Nasir et al., 2015 [181].
On a nal note, future research should also assess the effect of
currently used medication on mitochondrial quality control, as some
drugs may have agonistic or antagonistic functions. For example, pro-
pofol, a widely used sedative drug in patients admitted to ICUs, induces
mitochondrial dysfunction characterized by bioenergetic dysfunction
manifested by reduced ATP production and a reduced mitochondrial
mass in isolated human skeletal muscle cells [182]. Noradrenaline, a
commonly used vasopressor, increases mitochondrial network size and
turnover. Noradrenaline also reversed or prevented the occurrence
propofol-induced mitochondrial dysfunction and restored fatty acid
oxidation capacity. Although both propofol and noradrenaline reduced
mitochondrial membrane potential and amplied ROS production, their
combined effects were not additive at typical sub-maximal dosages used
in patients. Potentially, noradrenaline can prevent propofol-induced
impairment of mitochondrial function in human skeletal muscle cells
[182]. More importantly, the mainstay of current treatment – antibiotics
– also may or may not confer immunomodulatory and bioenergetic ef-
fects [183,184]. Given the hypothesis that mitochondria share a bacte-
rial ancestry, it is reasonable to consider the potential impact of bacterial
antibiotics on mitochondrial function. Research has demonstrated that
certain bacterial antibiotics can induce oxidative stress and harm in
mammalian cells [185]. This leads to issues like mitochondrial
dysfunction and excessive ROS (reactive oxygen species) production. It’s
worth noting that antibiotics have the potential to affect both the im-
mune system and the body’s energy processes [183]. This could
potentially impede the host’s ability to combat infections and maintain
organ function. Some of these adverse effects may stem from their
impact on mitochondria, which are already compromised due to the
underlying septic condition. However, it’s important to acknowledge
that the ndings from cell culture and animal models may not perfectly
align with results from clinical settings. For example, one study found no
discernible impact of antibiotics on the mitochondrial bioenergetics of
Fig. 6. Dysregulated mitochondrial dynamics in sepsis. In prolonged sepsis, the ssion-to-fusion ratio favours ssion. This imbalance causes the accumulation of
damaged mitochondria, oxidative stress, and cell death. Treatment with procyanidin B2 (PCB2) promotes Nrf2 translocation into the nucleus, which indirectly
upregulates mitochondrial fusion while inhibiting ssion [176]. Melatonin increases the activity and expression of SIRT3, which preserves mitochondrial quality
control mechanisms and alleviates sepsis-induced injury [177]. This highlights the potential therapeutic benets of targeting mitochondrial dynamics and quality
control in sepsis.
F.M. Lira Chavez et al.

Redox Biology 68 (2023) 102968
14
lymphocytes of septic patients [184]. In summary, are and will most
likely remain the main source of disease control in sepsis, and dis-
continuing their use is not a viable option, however antibiotics appear to
have an effect on mitochondrial function in vitro, and further research is
needed to corroborate these nding in clinical practice.
6. Conclusion
Sepsis-induced mitochondrial dysfunction is a complex process that
is primarily triggered by increased production of NO and ROS resulting
in oxidative stress, mitochondrial membrane damage, and ultimately,
cell death. Concomitantly, sepsis triggers release of mtDNA into the
circulation, propagating systemic inammation. Hereby, persisting
mitochondrial dysfunction and oxidative stress are major contributors to
the observed cell damage and organ dysfunction in sepsis.
Mitochondrial quality control (mtQC) is essential to mitigate organ
damage due to persisting mitochondrial dysfunction, diligently facili-
tating both repair mechanisms and the upkeep of mitochondrial integ-
rity. Mitophagy, the process of selective removal of damaged
mitochondria, is an essential mechanism for the maintenance of a
healthy pool of mitochondria. Inducing mitophagy reduces oxidative
stress, inammation, brosis, and organ injury in sepsis and attenuates
sepsis-induced muscle wasting. Sepsis leads to an imbalance between
ssion-fusion, favouring ssion over fusion and leading to the accu-
mulation of damaged mitochondria given the reduced rate of mitoph-
agy. Additionally, these processes combined with dysregulated
mitochondrial biogenesis underlies the reduction in mitochondrial mass
and persistence of mitochondrial dysfunction, leading to impaired bio-
energetics and loss of cellular homeostasis.
Overall, understanding the interconnectedness of mitochondrial
dysfunction and mitochondrial quality control over the course of sepsis
will provide the insights to develop targeted mitochondria-directed
therapies to prevent and recover from organ damage. Based on cur-
rent knowledge, preventing excessive mitochondrial ssion, while pro-
moting fusion and mitophagy during sepsis and stimulating biogenesis
timely after sepsis, may help attenuate organ dysfunction and improve
outcomes in sepsis.
Figures were created with BioRender.com.
Authors’ contributions
F.M. Lira Chavez and L.P. Gartzke performed the literature search,
analysed the articles, wrote the manuscript, and designed the gures. F.
E. van Beuningen participated in the extended literature search and the
information extraction. S.E. Wink participated in revising the manu-
script and designing the gures. G. Krenning, H.R. Bouma and R.H.
Henning participated interpreting the results and revising the manu-
script. All authors have read and agreed to the published version of the
manuscript.
Availability of data and materials
All data/literature analysed during this study are included in this
published article.
Financial Support and sponsorship
Funding bodies were not involved in the design of the study and
collection, analysis, and interpretation of data and in authoring the
article.
Ethical Approval and consent to participate
Ethical Approval is not applicable for this article.
Consent for publication
There are no human subjects in this article and informed consent is
not applicable.
Copyright
Authors retain copyright of their works.
Declaration of competing interest
The authors declare no potential conicts of interest with respect to
the research, authorship, and/or publication of this article. Funding
bodies were not involved in the design of the study and collection,
analysis, and interpretation of data and in authoring the article.
Data availability
No data was used for the research described in the article.
Acknowledgements
This work was supported by GUIDE and University Medical Centre
Groningen (PhD grant F.M.L.C and MD/PhD grant to L.P.G.) as well as
Consejo Nacional de Humanidades, Ciencias y Tecnologias (CON-
AHCYT) (PhD grant F.M.L.C). Many thanks to Nora Spraakman for her
valuable insights and contributions regarding readability and input.
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