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CoQ10 depletion: role in depression and depression-associated disorders.



Coenzyme Q10 (CoQ10) significantly contributes to many aspects of cellular functioning via its multiple roles as an antioxidant, a membrane stabilizer, and especially via mitochondria regulation, where it contributes to optimizing cell energy generation. Decreased CoQ10 is common in many CNS conditions, such as Parkinson's disease as well as a host of psychiatric conditions, including depression. Depression, in turn, increases the susceptibility for, or worsens the course of, many neurodegenerative conditions, including Alzheimer's disease. Rather than being a psychological reaction, recent work suggests that the biological processes underlying depression contribute to the aetiology and/or course of neurodegenerative conditions. Decreases in CoQ10 may be intimately associated with depression and such depression-associated conditions. Here we review the physiological roles that CoQ10 has in the course of depression and depression-associated conditions. These include impacts of CoQ10 on redox status, cell mediated immunity and subsequently on tryptophan catabolites (TRYCATs). By its regulation of fundamental cellular processes, CoQ10 modulates the activity of many organized systems, including immunity, allowing deficits in CoQ10 to have wide ranging effects. This chapter focuses on the role of CoQ10 in depression, but also in depression associated conditions, such as myalgic encephalomyelitis / chronic fatigue syndrome, Alzheimer's disease, fibromyalgia and Parkinson's disease.
George Anderson1
and Michael Maes2
1CRC Scotland and London, Eccleston Square, London, UK
2Deakin University, Department of Psychiatry, Geelong, Australia
Coenzyme Q10 (CoQ10) significantly contributes to many aspects of cellular
functioning via its multiple roles as an antioxidant, a membrane stabilizer, and especially
via mitochondria regulation, where it contributes to optimizing cell energy generation.
Decreased CoQ10 is common in many CNS conditions, such as Parkinson's disease as well
as a host of psychiatric conditions, including depression. Depression, in turn, increases the
susceptibility for, or worsens the course of, many neurodegenerative conditions, including
Alzheimer's disease. Rather than being a psychological reaction, recent work suggests that
the biological processes underlying depression contribute to the aetiology and/or course of
neurodegenerative conditions. Decreases in CoQ10 may be intimately associated with
depression and such depression-associated conditions. Here we review the physiological
roles that CoQ10 has in the course of depression and depression-associated conditions.
These include impacts of CoQ10 on redox status, cell mediated immunity and subsequently
on tryptophan catabolites (TRYCATs). By its regulation of fundamental cellular processes,
CoQ10 modulates the activity of many organized systems, including immunity, allowing
deficits in CoQ10 to have wide ranging effects. This chapter focuses on the role of CoQ10
in depression, but also in depression associated conditions, such as myalgic
encephalomyelitis / chronic fatigue syndrome, Alzheimer's disease, fibromyalgia and
Parkinson’s disease.
Keywords: Coenzyme Q10, depression, oxidative and nitrosative stress, cell-mediated
immunity, tryptophan catabolites, mitochondria
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George Anderson and Michael Maes
Coenzyme Q10 (CoQ10), (also called ubiquinone), is evident in all cells. CoQ10 is a
membrane stabilizer and a significant redox regulator, as well as being a vital cofactor in the
mitochondrial electron transport chain [1]. In mitochondria, CoQ10 contributes to adenosine
triphosphate (ATP) generation [2], thereby allowing CoQ10 to have a significant role in cellular
energy production and in optimizing cellular activity. Being an antioxidant, CoQ10 protects
cells from the ravages of oxidative and nitrosative stress (O&NS), a collective term for reactive
oxygen species (ROS) and nitrogen species (RNS).
CoQ10 has direct and indirect antioxidant effects, including the regeneration of oxidized
tocopherol and ascorbate, crucial to mitochondrial functioning [3]. CoQ10 is evident in vivo in
two forms: ubiquinol and ubiquinone, the reduced and oxidized forms respectively. The CoQ10
reductases, such as NAD(P)H: quinone reductase and NADH: cytochrome b5 reductase can
recycle ubiquinol from ubiquinone [4].
Given its role in core cellular processes, CoQ10 has many important physiological
functions, including: enhancing the repair of cell membranes [5]; modulating proinflammatory
gene transcription, by regulating the JAK/STAT signalling pathway and nuclear factor-κB (NF-
κB) transcriptional activity, thereby regulating inflammatory processes and apoptotic pathways
[6]; acting as a co-factor of uncoupling proteins [7]; and regulating wider genes associated with
cellular metabolism [8, 9].
Given these core cellular functions, depleted CoQ10 is associated with a number of
different medical conditions, including renal failure, cerebellar ataxia, infantile
encephalomyopathy and myopathy [reviewed in [10]. CoQ10 supplementation is therefore
useful across a host of disorders, with its efficacy being partly mediated by decreasing plasma
oxidative stress biomarkers, such as malondialdehyde [11], as well as increasing antioxidant
enzymes, including superoxide dismutase (SOD) and glutathione reductase [12].
Recent conceptualization of neuropsychiatric conditions have emphasized the role of
immune inflammatory processes, mitochondrial dysfunction and raised levels of O&NS [13].
Consequently decreased CoQ10 levels are evident in an array of such conditions, including
depression, myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), and
fibromyalgia [1, 14, 15]. Altered levels of ubiquinone or ubiquinol are also evident in many
neurodegenerative disorders, indicating a role in the pathophysiology of conditions such as
Alzheimer's disease and Parkinson's disease, which are both associated with increased immune
inflammatory activity, O&NS and alterations in energy metabolism [16, 17]. Likewise a
number of psychiatric conditions associate with suboptimal mitochondrial function, in
association with increased O&NS, including bipolar disorder (BD) and schizophrenia [18, 19,
20]. CoQ10 supplementation delays the functional decline in some of these diseases, perhaps
especially in Parkinson's disease [21, 10, 22].
Many of such neurodegenerative and psychiatric conditions are associated with increased
rates of depression. Recent work suggests that depression is not simply a psychological reaction
to such debilitating conditions, but rather that the biological processes underpinning depression
are intimately associated with this wide array of medical conditions per se [23]. As such,
diminished CoQ10 in depression [15] may have wider relevance to depression-associated
conditions, including Alzheimer's disease, Parkinson's disease, multiple sclerosis,
schizophrenia, ME/CFS and fibromyalgia [1, 11].
Coenzyme Q10 Depletion
In this chapter, we look at the role of CoQ10 depletion in depression and depression
associated conditions, including the evidence for the efficacy of CoQ10 supplementation in
such conditions.
Depression is a commonly diagnosed phenomenological state, with likely heterogeneous
biological underpinnings [24]. Classically, depression has been associated with decreased
levels of serotonin, with treatment by anti-depressants, such as selective serotonin reuptake
inhibitors, thought to mediate their limited efficacy by increasing serotonin availability and
serotonergic signalling centrally. However, anti-depressants also increase anti-oxidant levels
and modulate immune inflammatory activity [25], suggesting that some of their efficacy in the
management of depression has been serendipitous, via such processes.
Recent work has shown depressed patients to have increased levels of O&NS, immune
inflammatory indicants, such as pro-inflammatory cytokines, and alterations in mitochondrial
functioning [26, 27]. Many factors that regulate such processes are genetic susceptibility factors
for depression, including the melatonergic pathways and receptors [17]. Melatonin is derived
from serotonin, via the synthesis of N-acetylserotonin. As such, some of the efficacy of anti-
depressants may be mediated not simply by increasing serotonergic neuronal transmission, but
by increasing the availability of serotonin for melatonin synthesis [17]. Melatonin, like CoQ10,
is a powerful anti-oxidant and anti-inflammatory with mitochondria regulating functions [28].
As such, classical anti-depressant treatments may have been inadvertently targeting processes
strongly associated with CoQ10 functions.
It is of note that recent data suggests that the biological underpinnings of depression may
change over the course of recurrent episodes. The increased levels of O&NS in depression can
cause damage to membranes that leads to the exposure of neo-epitopes, in turn generating an
autoimmune response, including to the serotonergic pathways [29]. As such, the biological
underpinnings of depression change over the course of a lifetime for individuals with recurrent
episodes, driven by O&NS processes, with which CoQ10 is intimately associated. It is this
changing biological nature of recurrent depression that links depression with the
neurodegenerative disorders, including Alzheimer's disease [18, 30], as well as with other
psychiatric conditions, including schizophrenia [31]. By regulating processes of mitochondrial
functioning and O&NS regulation, CoQ10 impacts not only on the biological underpinnings of
depression but also as to how depression physiologically interacts with the aetiology and course
of other medical conditions.
O&NS in Depression
As indicated above, depression is associated with increased O&NS, including damage to
lipids, proteins and DNA, as well as increased immunoglobulin (Ig)G and IgM-mediated
autoimmune responses directed against neoepitopes that are generated by O&NS [18, 32, 33].
Such autoimmune responses can be directed against many types of neoepitopes, including
membrane fatty acids, neurotransmitters and anchoring molecules. Consequently, many
George Anderson and Michael Maes
biological processes can be altered, likely contributing to the heterogeneity in the course and
treatment of depression. Such changes over the course of depression, especially in recurrent
episodes, are termed as neuroprogressive in nature [32].
It should be borne in mind that ROS, RNS and nitric oxide (NO) are important to normal
physiological processes, including new learning associated long-term potentiation (LTP) and
wider intracellular and intercellular plasticity. As such, it is the balance of O&NS with
endogenous and dietary anti-oxidants that are important in determining as to whether
detrimental effects occur. Both unipolar and bipolar depressed patients show evidence of such
dysregulated redox signalling [18, 33, 34], which is supported by preclinical studies.
Increased O&NS markers in depression, include: malondialdehyde (MDA), which is a
marker of lipid peroxidation; 8-iso-prostaglandin F2(8-iso), which is a marker of arachidonic
acid peroxidation [35]; oxidative DNA damage, indicated by increased serum 8-hydroxy-2-
deoxyguanosine (8-OHdG) levels [35]; post-mortem oxidative RNA damage in the
hippocampus of depressed patients [36]; and telomere shortening [37, 38], which contribute to
ageing associated medical conditions. Studies conducted in depressed populations demonstrate
sustained increases in O&NS.
Such increased O&NS contributes to omega-3 fatty acid depletion in depressed patients
[39], an increased serum oxidant/anti-oxidant ratio [40], decreased antioxidant system
functioning, as indicated by lower levels of plasma vitamin E [41, 42] and vitamin C
concentrations [25], as well as reduction in wider antioxidants including zinc, glutathione
(GSH) and CoQ10 [15]. Concurrently lower levels of antioxidant-enzymes can occur in
depression, including superoxide dismutase (SOD) and glutathione peroxidase (GpX) [18].
Another antioxidant enzyme, paraoxonase 1 (PON1), which binds to high-density lipoprotein
(HDL), is also significantly decreased in unipolar, although apparently not in bipolar,
depression [43].
CoQ10 as Antioxidant
CoQ10 has some unique qualities, being the only lipid soluble antioxidant that is
endogenously synthesized, whilst mostly being present in its reduced form. There are at least
two processes by which CoQ10 can act as an antioxidant: firstly, by directly quenching lipid
peroxyl radicals [44]; and secondly, by indirectly regenerating other antioxidants, including α-
tocopherol from α-tocopheroxyl radicals [45]. The close proximity of CoQ10 to the factors
causing O&NS and its continual regeneration by reduction allows CoQ10 to have significant
protective effect on lipids and proteins, as well as DNA [46]. As such, CoQ10 is important to
maintaining membrane fluidity, in part by protecting cell membrane phospholipids from
oxidative damage and lipid peroxidation [47], including when given as a supplement to human
volunteers [48] and patients with heightened O&NS and immune inflammatory markers [49],
whilst also increasing serum antioxidants, glutathione, catalase and SOD. Given its inhibition
of lipid peroxidation and the oxidant, 4-hydroxy-2-nonenal (4HNE), it is not unlikely that
CoQ10 will prevent the 4HNE mediated conformational change in sirtuin-3, allowing CoQ10
to prevent the 4HNE mediated decrease in sirtuin-3 function [50]. Sirtuin-3 localizes to
mitochondria and is important to many aspects of mitochondrial function. Lipid peroxidation
damages DNA, leading to the induction of poly (ADP-ribose) polymerase-1 (PARP-1). PARP1
induction depletes nicotinamide (NAD+), thereby decreasing sirtuin-1 and peroxisome
Coenzyme Q10 Depletion
proliferator-activated receptor gamma co-activator-1 alpha (PGC-1"), which are classically
viewed as master regulators of mitochondria [51]. As such, by its regulation of O&NS and lipid
peroxidation, CoQ10 may indirectly regulate sirtuin levels, in turn modulating mitochondrial
function. Mitochondrial energy production and ROS may also act to regulate CoQ10 [52],
suggesting reciprocal interactions.
However, it should be noted that CoQ10 can have biphasic effects on ROS production,
showing both pro-oxidant [53] as well as antioxidant effects [54]. Oxidized CoQ10 acts as a
prooxidant in the genesis of hydrogen peroxide (H2O2) and superoxide (O2-), the generation
of which are crucial to normal cell functioning and redox state regulation, by driving changes
in transcription [55] that are relevant to cellular plasticity and signalling, including centrally
[56]. With the redox state of CoQ10 varying in line with the cell's redox potential as well as
with mitochondrial membrane potential, the redox state of CoQ10 acts as a marker of the cell's
metabolic state and needs. H2O2 functions as an intracellular second messenger
communicating cellular needs with the mitochondrial and nuclear genomes in real time [55].
Depression and Immune Inflammation
As antioxidants, such as CoQ10, zinc and GSH, have anti-inflammatory effects, decreases
in antioxidants evident in depression will increase wider immune inflammatory processes [18].
Moreover, decreased antioxidants enhance the transcription of the pro-inflammatory cytokines
IL-1, IL-6, and tumor necrosis factor-alpha (TNF-α) [57], allowing decreased CoQ10 to be
associated with wider inflammatory processes in depression.
Cell Mediated Immunity in Depression
As indicated above, O&NS are highly interactive with immune system activity. This
includes changes in autoimmunity driven O&NS damage to membranes that creates neo-
epitopes. O&NS is also highly interactive with cell mediated immunity (CMI), which is
important in driving changes in central and peripheral tryptophan catabolites (TRYCATs),
which, in turn, regulate neuronal activity and neuronal interarea patterning changes in
depression [13]. In this context neuronal activity may be perceived as a form of immune-to-
immune communication, with central glia being CNS immune-type cells [58]. We will briefly
review CMI and look at its role in depression, before looking at the role of CoQ10 in the
regulation of immune responses.
Cell Mediated Immunity
CMI involves monocytes/macrophages and T-cells, and the interactions of these cells. Put
simply, CMI is the part of the immune system that does not involve antibodies. It should be
emphasized that oxidant status is highly interactive with CMI and inflammatory processes.
When activated by an antigen, T-cells produce IL-2 and interferon-gamma (IFN-ү) as well
as increasing their expression of the IL-2 receptor (IL-2R). IL-2 can then stimulate proliferation
George Anderson and Michael Maes
and differentiation, thereby inducing T cell activation. Serum IL-2R p55 is commonly used as
an indicant of T cell activation and IL-2 production [59]. The activation of CMI is also indicated
by released neopterin level, which is released from monocytes/ macrophages that have been
activated by IFN-ү and IL-2 derived from T-cells. IL-2 levels are increased in depressed
patients [60]. Other CMI activation markers include: increased TNF-α, as well as its cleaved,
soluble receptors (sTNFr1 and sTNFr2); serum sCD8 levels and IL-6, which often associate
with enhanced sIL-2R and neopterin levels; increased IL-12, IL-1β and IL-18, the latter two
factors being released following inflammasome activation. Generally, IL-2, IL-12, IFN-ү,
neopterin and sTNFr2 are indicative of an elevated Th-1 response, with increases in IL-4 and
IL-10 indicative of a Th-2 response, whilst increases in TGF-β indicate a Th-3/regulatory T-
cell response. Raised levels of IL-1β are counteracted by increases in the IL-1 receptor
antagonist (IL-1RA), with increases in both generally indicative of a relatively elevated
monocyte/macrophage wing of CMI activation. Both IL-1β and IL-1RA are increased in
depression [61]. As such, depression can be viewed as a CMI disorder that is driven by O&NS
and the interactions of immune-inflammatory activity and O&NS [62].
CMI and Depression
CMI, in association with O&NS, has been intimately associated with depression for a
number of years [63, 64, 65], evidenced by: increased serum sIL-2R and sCD8 molecule; raised
levels of activated T cells; higher stimulated production of IFN-ү and IFN-ү/IL-4 ratio; raised
levels of neopterin and sTNFR-1 or sTNFR-2; increased IL-12 levels [66]. Post-mortems of
medication-free depressed patients show increased IL-2, IL6, IL12A, IL-18, IFN-ү and TNF-α
in the prefrontal cortex, as well as evidence of increased apoptotic processes, coupled to a
decrease in antioxidants [67]. These results highlight the concurrent changes occurring
centrally in depression, including those involving inflammation, apoptosis and oxidative stress.
Such data also highlights the role of interactions of CMI with O&NS in depression, as well as
hinting at apoptotic processes that have led to depression being conceptualized as a
neuroprogressive disorder. The number of previous episodes of depression positively correlates
with serum IL-1β, TNF-α and neopterin levels, suggesting a role for CMI interactions with
O&NS in the aetiology and course of recurrent depression and neuroprogression. This is
important given the data showing that recurrent depression increases the risk of Alzheimer's
disease [68]. However, it should be noted that changes in plasma IL-2 and IFN-ү levels are not
always evident in depression [69], perhaps indicative of the heterogeneous nature of the
disorder or of different stages of chronicity and neuroprogression.
It is worth saying a few words about the nature of neuroprogression. Neuroprogression is
a stage related process that is potentially progressive, and which involves neurodegeneration in
association with reduced neurogenesis and neuronal plasticity, coupled to increased levels of
apoptosis [34]. A number of psychiatric conditions that were once thought to be static or with
stress associated psychological factors that contributed to changes over the course of chronicity,
are now thought to be neuroprogressive, including schizophrenia and bipolar disorders, as well
Coenzyme Q10 Depletion
as depression [34]. The risk of neuroprogression in depression is associated with longer illness
duration and the recurrence of depressive episodes. Increases in recurrent episodes associate
with decreases or loss of treatment response [62]. Given that a 2-3% decrement in some
cognitive measures is associated with each depressive episode, accumulating detrimental
effects are likely to occur in recurrent depression, with increased frequency of depressive
episodes enhancing the risk of Alzheimer's disease [70]. Consequently, recurrent depression
associates with a number of structural brain changes, including volume reductions in the
hippocampus and basal ganglia, as well as in the orbitofrontal and subgenual prefrontal cortices
[71]. Longer illness duration associates with a general decrease in the volume of cerebral grey
matter. Two meta-analyses highlighted the association of recurrent episode frequency with
hippocampal volume in recurrently depressed patients [72, 73], with the level of hippocampal
volume loss correlating with neurocognitive losses.
Neuroprogression in depression is at least partly driven by increased O&NS [62] and CMI,
with a role for IL-1β, TNF-α, IFN-ү and IL-2, as well as TRYCATs, such as the excitotoxic
quinolinic acid (QUIN) [62, 74], as detailed below. As well as concurrently contributing to
autoimmunity that alters the nature of the immune responses over recurrent episodes, a decrease
in the counterinflammatory ‘compensatory (anti)-inflammatory reflex system’ (CIRS) with
disease progression occurs, contributing to a dampened negative feedback, which further
heightens the O&NS and CMI inflammatory processes, driving neuroprogression [75]. Such
data is pertinent not only to the changes occurring over the course of depressive episodes, but
also says something about the biological underpinnings in the aetiology, course and
management of depression-associated conditions, such as the dementias.
CoQ10: Role in Inflammation and CMI
As well having impacts on mitochondrial functioning in immune cells, thereby regulating
immune cell activity (see below), CoQ10 also regulates the expression of many genes and
transcription factors that underlie CMI and inflammatory responses, including: TNF-α;
chemokine (C-X-C-motif) ligand 2 (CXCL2); chemokine (C-C-motif) ligand 3 (CCL3); NF-
κB transcription of inflammatory genes; lipopolysaccharide (LPS)-induced chemokines such
as macrophage inflammatory protein-1 alpha and RANTES (Regulated upon activation, normal
T cell expressed and secreted); and LPS-sensitive genes that are implicated in the regulation of
signal transduction and cell proliferation pathways, as well as transcriptional regulation [76,
77]. Importantly, CoQ10 can suppress nuclear factor of activated T cells (NFATc1) as well as
NF-κB signalling [78]. Such effects of CoQ10 highlight its importance in CMI and immune
inflammatory processes that are relevant to the aetiology and course of depression and that
provide a link of depression to depression-associated conditions, such as Alzheimer's disease
and cardiovascular disorders (CVD) [30].
Animal studies also provide support for a role of CoQ10 in depression-associated CMI and
inflammatory processes. Ubiquinol administration to mice induces PPARα associated genes as
well as regulating fatty acid metabolism and inflammation [77].
CoQ10 administration to rats lowers O&NS levels, as well as decreasing the release of pro-
inflammatory cytokines, including TNF-α and IL-1β [79].
Given such antioxidant and anti-inflammatory effects, it may seem unusual that CoQ10
supplementation can have activating effects on immune cell functioning, including
George Anderson and Michael Maes
immunoglobulin (Ig)G, and the numbers and/or function of macrophages and T-cells, including
the CD4/CD8 T-cell ratio [80, 81, 82]. Such effects have been proposed to underlie the increase
in infection resistance associated with CoQ10 [83]. This may allow for some parallels to be
drawn between the effects of CoQ10 and melatonin. Melatonin is likewise a powerful
antioxidant, anti-inflammatory and mitochondrial regulator that also has activating effects on
the immune system, increasing Th1 responses and natural killer cell responses [84]. However,
as with CoQ10 this is accompanied by a sharper and more efficient transient immune response,
rather than a prolonged and chronic immune response that is more typically associated with
Th17 cells.
As well as direct effects on neuronal functioning and survival, both O&NS and CMI
modulate neuronal survival, plasticity and functioning, as well as neurogenesis, via changes in
TRYCATs. TRYCATs are predominantly synthesized and released by astrocytes and microglia
in the CNS. Glia collate information in the CNS and significantly regulate, if not control,
neuronal activity and functioning. TRYCAT fluxes are one means by which glia achieve this.
Depression is classically associated with decreased serotonin, with serotonin levels being
largely determined by the levels of its precursor, tryptophan. The TRYCAT pathways also
require tryptophan as a precursor. As such, heightened TRYCAT pathway activity can decrease
tryptophan availability for serotonin synthesis, contributing to the decreased serotonin levels
evident in depression. In normal physiological functioning, over 95% of tryptophan is used in
the synthesis of TRYCATs, and is therefore unavailable to act as a precursor for serotonin
synthesis. It should be noted that serotonin itself acts as a precursor for N-acetylserotonin
(NAS) and melatonin synthesis. Considerable interest is now being generated as to the role of
NAS and melatonin in depression, with both having significant impacts on mitochondria
functioning, partly replicating some of the effects of CoQ10. As such, heightened TRYCAT
pathway activity contributes to the depletion of serotonin, NAS and melatonin, as well as to the
production of neuroregulatory TRYCATs [13].
TRYCAT pathway activity is driven by two enzymes, indoleamine 2, 3-dioxygenase (IDO)
and tryptophan 2, 3-dioxygenase (TDO). Both of these enzymes initially catalyse the synthesis
of kynurenine (kyn) from tryptophan. IDO is mainly activated by IFN-ү, and to a lesser degree
by IL-1β, TNF-α and IL-18 [85]. As highlighted above, depression is associated with increases
in all of these IDO inducers. TDO is mainly induced by the hypothalamic-pituitary-adrenal
(HPA) axis derived stress hormone cortisol, which is often dysregulated in depression [86].
IDO is expressed in many different cells and tissues. IDO has an important role in
determining immune response patterning, especially via its activity in dendritic cells, which are
crucial in driving regulatory T-cell production. The balance of regulatory T cells with the more
proinflammatory T-helper (Th)1 and autoimmune and prolonged inflammation associated
Th17 cells is important to the duration and extent of immune responses, as well as being
relevant to antidepressant effects [87]. IDO is predominantly expressed centrally in microglia
and infiltrating peripheral immune cells. TDO is very highly expressed in the liver, as well as
within central astrocytes and some neurons.
Coenzyme Q10 Depletion
An increase in the kyn/tryptophan ratio is commonly found in depressed patients,
particularly when somatization symptoms are comorbid [88]. Such relative increases in kyn are
predominantly a consequence of heightened IDO activity, concurrently driving down levels of
serotonin, NAS and melatonin synthesis. Decreased melatonin synthesis may be of some
importance to both O&NS and CMI activation levels as autocrine melatonin is a significant
inhibitor of immune cell inflammatory activity [89], as well as being a powerful antioxidant
and significant inducer of endogenous antioxidants [13]. Over 60% of kyn in the CNS is
peripherally derived, suggesting powerful effects of systemic immune system activity on
central glia regulation of neuronal activity and patterning. Following IDO or TDO activation,
kyn can be effluxed from cells or further catabolized within the same cell or within another
cell, following kyn uptake. Kyn may then be catabolized to kynurenic acid (KYNA) via
kynurenine 2, 3-aminotransferase (KAT) activity. The kyn/KYNA ratio is therefore determined
by KAT activity. In predominantly TDO expressing cells, such as astrocytes and some neurons,
kyn and KYNA are the main TRYCATs produced. However, in IDO-expressing cells, further
processing along the TRYCAT pathways leads to the synthesis of a wider range of
neuroregulatory TRYCATs, including: kynurenine 3-monooxygenase (KMO), a significant
negative regulator of neurogenesis [90]; the excitotoxic QUIN; and 3-hydroxyanthranilic acid
production, which, by depleting GSH in activated T-cells, leads to activated T-cell death.
Overall, the activation of TRYCAT pathways can be co-ordinated with changes in a
number of other processes, all of which are relevant in depression and in depression associated
conditions. TRYCAT pathway activation depletes tryptophan, thereby lowering serotonin,
NAS and melatonin levels, whilst enhancing the synthesis of a variety of TRYCATs that can
have differential effects on neuronal activity and survival, as well as neurogenesis. As such,
IFN-ү, cytokines and cortisol induced TRYCATs, to some extent, co-ordinate the effects of
CMI, O&NS and stress in depression, via impacts on glia and glia regulation of neuronal
activity. For example, KMO inhibition prevents the decreased neurogenesis driven by IL-1β,
highlighting a role for the TRYCAT pathways in determining the effects of immune-
inflammatory processes in the inhibition of neurogenesis, an important event in depression and
depression-associated disorders.
TRYCATs and Depression
Lowered plasma L-tryptophan level is one of the most robust biological finding in
depressed patients. Decreased plasma tryptophan availability in relation to immune-
inflammatory biomarkers in depressed patients was first published by Maes and colleagues,
who showed that its level could be explained by increases in immune-inflammatory biomarkers
[91]. Subsequent work has confirmed the importance of TRYCATs in depressed patients.
Depressed patients show increases in the neurotoxic TRYCATs, kyn and QUIN, whereas the
potentially neuroprotective KYNA is decreased, when measured in the periphery [88].
Generally, enhanced kyn levels increase anxiety and depression. As well as QUIN, other
TRYCATs may also be excitatory, including picolinic acid. Increases in such TRYCATs, when
coupled to the effects of KMO in mediating the IL-1β inhibition of neurogenesis, allows the
TRYCATs to be intimately associated with conceptualizations of neuroprogression in
depression, thereby linking to depression-associated conditions such as Alzheimer's disease.
QUIN is increased in the anterior cingulate of depressed suicide patients [92], with QUIN likely
George Anderson and Michael Maes
being derived from microglia [93]. Increased IDO and lowered tryptophan are also evident in
the early stages of depression, as evidenced by these changes in melancholic adolescents [94].
With decreased antioxidants and increased oxidative stress in depressed patients, it is
interesting to note that IDO utilizes the superoxide anion, and therefore can also be seen as an
antioxidant enzyme. As such IDO induction can be viewed as an antioxidant defence following
O&NS [95]. This suggests that IDO induction and TRYCAT pathway activation may be at least
partly determined by raised levels of O&NS and lowered antioxidants, as well as by CMI and
O&NS induced pro-inflammatory cytokines. This may imply that CMI and O&NS have
evolved to regulate neuronal activity and patterning, partly via TRYCATs, in response to
suboptimal environmental challenges, such as stress and dietary restricting factors.
Raised levels of peripheral inflammation increase kyn production, thereby raising KYNA
synthesis in the CNS. Among other effects, KYNA inhibits the alpha 7 nicotinic acetylcholine
receptor (α7nAChr), which leads to decreases in cortex ACh, glutamate and dopamine release,
thereby contributing to suboptimal cortex arousal and therefore to cognitive deficits [96]. The
α7nAChr is also a significant regulator of mitochondrial functioning [97], and is positively
regulated by melatonin [98]. As such some of the deficits in depression, including cognitive
and emotional, may be mediated by the multiple consequences arising from increased
TRYCAT synthesis, including decreased melatonin and suboptimal mitochondrial functioning.
It is also of note that decreased α7nAChr level and activity can lower the reactivity threshold
for a number of CNS cells, including astrocytes, microglia and perivascular mast cells [99],
with the latter likely contributing to blood-brain-barrier (BBB) permeability and the activation
of invading leukocytes. This suggests that peripheral inflammation in depressed patients,
perhaps especially when associated with increases in somatization symptoms, will modulate
not only cognitive functioning but also central immune and glia reactivity threshold, as well as
BBB permeability, thereby having modulatory effects on leukocyte extravasation, central
inflammatory levels, neuroprogression and processes classically associated with
neurodegenerative disorders. Recent data has shown a role for increased gut permeability in the
aetiology and course of depression [100]. The above would be some of the likely downstream
mechanisms whereby increased gut permeability, by inducing immune inflammatory activity,
contributes to the changes occurring in depression.
Raised levels of KYNA would also inhibit the α7nAChr activation in regulatory T cells,
thereby decreasing the immune modulatory, generally immune suppressive, effects of
regulatory T-cells [101]. As such, this would be expected to contribute to enhanced levels of
CMI associated cytokines and to increase Th17 activity in depressed patients [102]. Overall,
many depression associated changes are driven by O&NS and CMI activation that act via the
regulation of central and peripheral TRYCATs. Changes in mitochondrial functioning may be
both upstream and downstream of such co-ordinated O&NS, CMI and TRYCAT effects.
CoQ10 and TRYCATs
Currently there is no direct data pertaining to the effects of CoQ10 on TRYCATs, either
centrally or peripherally. Given the antioxidant, anti-inflammatory and mitochondria regulating
effects of CoQ10, it is not unlikely that at least indirect effects on TRYCAT regulation will be
found. This will be important to determine in future experiments, given the important role that
TRYCATs have in co-ordinating the effects of O&NS and CMI on neuronal activity and
patterning. The relevance of CoQ10 is highlighted by its beneficial effects on neurogenesis that
Coenzyme Q10 Depletion
has been inhibited by Alzheimer's disease associated amyloid B [103]. These authors found
that CoQ10 prevented the inhibitory effects of amyloid B on neurogenesis, by increasing the
phosphatidylinositol 3-kinase (PI3K) pathway, subsequently increasing levels of glycogen
synthase kinase (GSK)-3β, which would be expected to increase levels of nuclear factor
(erythroid-derived 2)-like 2 (Nrf2), thereby increasing endogenous antioxidant levels. CoQ10
may be differentially expressed and taken up in different brain regions [104], suggesting that it
could have significant impacts on changes in central interarea patterning that are altered in
depression and depression associated conditions. As such, CoQ10 is likely to have many
impacts on a variety of processes in different cell types that would be relevant to the regulation
of TRYCATs and TRYCAT mediated effects in depression and depression associated
Depression: CoQ10 and Mitochondrial Functions
Mitochondrial dysfunction is associated with many psychiatric conditions, including
depression [26]. Mitochondria are also a significant source of ROS, especially the superoxide
anion, which is rapidly converted to H2O2. As well as having pro-oxidant properties, H2O2 is
highly membrane permeable and therefore can readily act as an intercellular signalling factor,
allowing the status of mitochondrial functioning to have both intracellular and intercellular
signalling consequences. Its role as an antioxidant coupled to its optimization of mitochondrial
functioning are two key inter-related factors that underlie the efficacy of CoQ10 in depression
and depression associated conditions.
Additionally, mitochondria are crucial to T-cell functioning, suggesting that changes in
CMI and immune driven cytokines and inflammation that occur in depression may be
associated with alterations in mitochondrial functioning [105]. Likewise optimized
mitochondrial functioning is critical to the appropriate activation of macrophages and
monocytes [106], suggesting that the macrophage/monocyte wing of CMI is also subject to
variation that is driven by alterations in CoQ10 levels. Similarly, dendritic cells, key
determinants of regulatory T-cell functioning and therefore of the balance of T-cell
inflammatory and anti-inflammatory activations, are also subject to differential regulation that
is dependent on mitochondrial functioning [107]. As such, the regulation of mitochondrial
functioning in immune cells, as well as in glia and neurons, is likely to be relevant to the effects
of CoQ10 in depression and depression associated conditions.
The above effects in immune cells is due to the vital role that CoQ10 plays in mitochondrial
respiratory chain functioning, where it acts as an electron carrier from complexes I and II to
complex III of the electron transport chain, thereby being crucial for ATP synthesis [108].
When the electron transport chain is dysregulated, mitochondrial oxidative capacity is
compromised, culminating in diminished levels of energy production [109]. In addition to
energy production, CoQ10 is also involved in cellular membrane redox chains [110], which act
to remove the excess reducing power driven by glycolysis adoption when mitochondrial
respiration is reduced [111].
CoQ10 is also important to the functioning of the two main complexes (I and III) that are
involved in mitochondrial ROS production [112], which contributes to mitochondrial
regulation of cellular plasticity.
George Anderson and Michael Maes
It is also important to note that the stability of complex III in the mitochondrial membrane
is partly determined by CoQ10 [113].
CoQ10 deficiency, as found in many depressed patients, can also decrease mitochondrial
complexes II, III and IV of the electron transport chain in association with decreased levels of
proteins within mitochondria that underpin oxidative phosphorylation, thereby contributing to
a reduced mitochondrial membrane potential [114]. As a consequence of decreased CoQ10
leading to increased ROS, there is also an increased likelihood of mitochondrial permeability
transition pore formation, ultimately leading to mitophagy and increased apoptosis [114]. It is
important to note that such abnormalities are restored, at least partially, by CoQ10
supplementation [114].
Impaired mitochondrial function coupled to increased O&NS, CMI and fatigue are
associated with a number of human medical conditions, including ME/CFS, fibromyalgia,
Parkinson's disease, Alzheimer's disease and multiple sclerosis [1, 115, 116]. All of these
conditions are associated with increased levels of depression. Mitochondrial mutations or
impaired complex I activity, can also lead to severe fatigue, including in muscles [117]. CoQ10
effects at complex I may be particularly important to effects on fatigue, with relevance to
differentiating the biological underpinnings of specific symptoms in conditions such as
fibromyalgia [118].
CoQ10 and Mitochondrial Gene Regulation
Mitochondrial biogenesis involves a complex interaction of the nuclear and mitochondrial
genomes, involving an array of transcription factors that drive genes that encode enzymes
regulating a plethora of factors, including fatty acid oxidation, anti-oxidant defences and
oxidative phosphorylation [1].
In humans, CoQ10 modulates the transcription of hundreds of genes [119] that are
associated with many crucial aspects of cellular functioning, including stimulating transcription
of PGC-1α, which is a major inducer of Nrf2 and the antioxidant response element (ARE) gene
activation, in turn driving endogenous antioxidant production. Such data implicates a role for
CoQ10 in the regulation of bioenergetics, cellular redox status and mitochondrial biogenesis
[120, 121].
PGC-1α also indirectly modulates mitochondria DNA transcription, increasing
mitochondrial transcription factor A (Tfam). The longevity associated proteins, the sirtuins are
also significant regulators of PGC-1α [122].
As to whether CoQ10 has any impact on sirtuin levels requires investigation, as this would
more directly link CoQ10 with the ageing process, which contributes to the susceptibility to
most medical conditions.
Relevance in Wider Depression-Associated Medical Conditions
With depression being classically conceptualized in psychological terms, predominantly as
an emotional response to stress, the association of depression with an array of other medical
conditions has often been attributed to the stress of having a poorly treated medical condition,
such as Alzheimer's disease or cancer. Stress undoubtedly can trigger depression, with
relatively minor stressors, such as examination stress increasing oxidative damage to DNA and
Coenzyme Q10 Depletion
membrane fatty acids, as well as lowering total antioxidant status [123]. Stress can have a
variety of impacts, including in the context of different models of depression. For example,
chronic stress induced increases in gut permeability may lead to the leakage of gut bacteria or
small fragments of partially digested food that trigger a local immune inflammatory response,
with consequential increases in central inflammatory factors, including cytokines. Chronic,
although not acute cortisol/stress, can also increase monoamine oxidase, leading to heightened
breakdown of monoamines including serotonin, in glia [124, 125], thereby decreasing levels of
NAS and melatonin, which may be relevant for glia reactivity levels, as found for macrophages
[126]. As such, the biological underpinnings of the stress response allow for a better integration
of stress with the biological processes underpinning depression, in turn shifting
conceptualizations of depression from that of a psychological reaction to a severe medical
condition, to one that emphasizes the roles of stress and depression in the pathophysiological
aetiology and course of a diverse array of medical conditions. A role for stress driven
depression is relevant to the aetiology and course of many medical conditions, including
Parkinson’s [116], schizophrenia [31], Alzheimer's disease and multiple sclerosis, as well as
other human conditions such as those occurring in the postpartum period [127] and in early
development [128]. All of these medical conditions show increases in O&NS, CMI activation
and suboptimal mitochondrial functioning, in association with increased levels of depression.
As such, depression is less of a psychological comorbidity and more an intimate part of the
pathophysiology underpinning many medical conditions, interwoven by changes that involve
O&NS, CMI, TRYCATs and mitochondrial regulation, with differentiation of these conditions
being driven by variability in specific susceptibility genes and epigenetic influences [13].
Consequently, CoQ10 may be expected to be intimately linked to a host of medical conditions,
which wide bodies of data support. This integrated association of depression with the processes
underpinning the aetiology and course of other medical conditions may explain in biological
terms how a period of stress induced depression often predates symptom exacerbations across
a host of medical conditions, including in multiple sclerosis, Parkinson’s disease and
schizophrenia [18, 129].
CoQ10 Treatment of Depression and Depression-Associated Conditions
Data shows reduced plasma CoQ10 levels in depressed patients [15], with decreased
CoQ10 being highly linked to antidepressant treatment resistance, as well as with higher levels
of fatigue symptoms. Interestingly, this study showed that 51.4% of patients with depression
had levels of plasma CoQ10 that were lower than the lowest values measured in healthy
controls. Concurrently ATP levels and mitochondrial mass were also relatively decreased, with
lipid peroxidation, an indicant of O&NS associated damage, being increased [130]. These
authors also suggested that the antidepressant amitriptyline may aggravate CoQ10 depletion.
In older patients with bipolar disorder associated depression, an open label study showed
relatively high CoQ10 supplementation to have significant antidepressant effects, suggested to
be mediated by effects on mitochondrial bioenergetics [131].
Decreased plasma CoQ10 levels have also been shown in ME/CFS [15, 132], where it
associates with symptoms of fatigue, poor concentration, impaired memory and autonomic
symptoms [15]. Lower CoQ10 levels may contribute to the decreased longevity evident in
ME/CFS, especially via its association with CVD [15, 133]. CoQ10 supplementation may be
George Anderson and Michael Maes
especially efficacious for ME/CFS patients with exercise intolerance, especially when
increased O&NS is also present [134]. Decreased CoQ10 is also evident in blood-derived
mononuclear cells of fibromyalgia patients [135], with plasmaCoQ10 in juvenile fibromyalgia,
negatively correlating with O&NS as well as hypercholesterolemia [136]. The latter may
mediate some of the association of lowered CoQ10 with CVD. CoQ10 supplementation can
significantly improve the quality of life fibromyalgia patients [137], suggested to be partly
mediated by increased mitochondrial biogenesis [118]. Parkinson's disease patients also show
significant decreases in CoQ10, in both mitochondria [138] and plasma [139]. CoQ10
supplementation may slow Parkinson’s disease symptom progression [140], with CoQ10
supplementation slowing the loss of dopamine neurons in Parkinson’s disease patients [141],
although not all studies show a benefit of CoQ10 in Parkinson's disease patients [142]. A
number of studies have shown statins to increase fatigue and other ME/CFS symptoms via a
significant lowering of plasma and muscle CoQ10 levels [143], with CoQ10 supplementation
showing utility in offsetting such statin side-effects, including statin-induced musculoskeletal
pain [144], muscle weakness and cramps, as well as fatigue [145]. Interestingly, statins have
been suggested to offset the development of Parkinson’s disease [146], which, when coupled
to the high levels of depression for which amitriptyline may be prescribed, suggests that two
not uncommonly used medications in Parkinson’s disease may contribute to lowering CoQ10,
perhaps inadvertently contributing to the course of Parkinson's disease. Melatonin has been
proposed to have efficacy in host of mitochondria-associated medical conditions, including
Parkinson's disease [17]. It is interesting to note that melatonin benefits may be partly via the
maintenance of CoQ10 levels [147]. A number of factors are known to regulate CoQ10
synthesis, including ROS and mitochondrial energy production, generally involving the PGC-
1α/sirtuin path [148]. As to whether melatonin's regulation of sirtuin-1 [149] contributes to
CoQ10 regulation or as to whether some other aspects of melatonin's effects are relevant
requires investigation.
It should be noted that the dose of CoQ10 used in many studies is variable. Studies that
have focussed on different CoQ10 concentrations have generally found that only the highest
levels used, perhaps as high as 2,400 mg/day, prove of clinical utility, including in Parkinson's
disease patients [150].
CoQ10 is intimately associated with many facets of depression, including O&NS, CMI and
TRYCATs. Many of its effects are mediated by its influence on mitochondrial functioning,
with relevance for a wide array of depression-associated conditions.
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Supplementary resource (1)

... As such, proteins and fatty acids in cell membranes can be attacked by ROS, which reduces membrane fluidity and diminishes the performance of cell-membrane receptors and ion channels, thus disrupting intercellular and intracellular signaling processes and leading to such disorders as fatigue, hyperalgesia, depression, and neurodegenerative processes. 27,32,33 Also, in depleted levels of CoQ 10 , uncoupling proteins do not function correctly, which causes inability in regulating cellular fuel metabolism and other ATP-dependent processes. 27,34 Some genes involved in mitochondrial biogenesis and replication due to increasing energy demands are under CoQ 10 control. ...
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Background: Survival rates among breast cancer patients and the number of patients living with treatment side effects have improved, leading to increased focus on quality of life (QOL). The objective of this study was to determine the efficacy of CoQ10 on QOL scores among breast cancer patients in Iranian undergoing tamoxifen therapy. Methods: Thirty breast cancer patients were randomized into two groups. The first group received 100 mg CoQ10, and the second group took fplacebo once a day for 8 weeks. QOL was evaluated by a standard QOL questionnaire and a specific questionnaire on QOL of breast cancer patients at baseline and the end of the study. Also, physical activity of patients was assessed with the IPAQ questionnaire and dietary intake determined by a 3-day dietary record. Results: The data of 30 subjects were analyzed. According to QOL C30 data, CoQ10 led to a significant increase in physical functioning (P=0.029), emotional functioning (P=0.031), and cognitive functioning (P=0.023) compared to placebo. Symptom scales revealed a notable reduction in appetite loss in the first group (P=0.01). Global health status showed no significant changes in either study arm. On the QOL BR23, progress in functions and decline in symptoms were not statistically significant. Arm symptoms showed significant reduction (P=0.022) in patients that received placebo. Conclusion: This trial indicates that CoQ10 supplementation has effects in ameliorating some dimensions of QOL in breast cancer patients. To generalize the results, larger and longer intervention studies are needed. Clinical trial registration: IRCT2015042021874N1.
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Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium- induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10μM) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased ROS production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity.
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T cells play a central role in host defense. ATP release and autocrine feedback via purinergic receptors has been shown to regulate T cell function. However, the sources of the ATP that drives this process are not known. We found that stimulation of T cells triggers a spike in cellular ATP production that doubles intracellular ATP levels in <30 s and causes prolonged ATP release into the extracellular space. Cell stimulation triggered rapid mitochondrial Ca2+ uptake, increased oxidative phosphorylation, a drop in mitochondrial membrane potential (Δψm), and the accumulation of active mitochondria at the immune synapse of stimulated T cells. Inhibition of mitochondria with CCCP, KCN, or rotenone blocked intracellular ATP production, ATP release, intracellular Ca2+ signaling, induction of the early activation marker CD69, and IL-2 transcription in response to cell stimulation. These findings demonstrate that rapid activation of mitochondrial ATP production fuels the purinergic signaling mechanisms that regulate T cells and define their role in host defense.
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For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical use of CoQ10. Also at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ10 levels, as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
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Background Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder. Methods For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes. Results Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala. Conclusions The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.
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Background Telomere shortening is a normal age-related process. However, premature shortening of telomeres in leukocytes – as has been reported in depression – may increase the risk for age-related diseases. While previous studies investigated telomere length in peripheral blood mononuclear cells (PBMCs) as a whole, this study investigated specific changes in the clonal composition of white blood cells of the adaptive immune system (CD4+ helper and CD8+ cytotoxic T lymphocytes, and CD20+ B lymphocytes). Methods Forty-four females with a history of unipolar depression were investigated and compared to fifty age-matched female controls. Telomere lengths were compared between three groups: 1) individuals with a history of depression but currently no clinically relevant depressive symptoms, 2) individuals with a history of depression with relevant symptoms of depression, and 3) healthy age-matched controls. Telomere length was assessed using quantitative fluorescence in situ hybridization (qFISH). Results Both groups with a history of unipolar depression (with and without current depressive symptoms) showed significantly shorter telomeres in all three lymphocyte subpopulations. The effect was stronger in CD8+ and CD20+ cells than in CD4+ cells. Individuals with a history of depression and with (without) current symptoms exhibited a CD8+ telomere length shortening corresponding to an age differential of 27.9 (25.3) years. Conclusions A history of depression is associated with shortened telomeres in the main effector populations of the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression independently of the severity of depressive symptoms. CD8+ cytotoxic T cells and CD20+ B cells seem to be particularly affected in depression. The total number of depressive episodes did not influence telomere length in the investigated adaptive immune cell populations.
Much evidence indicates that superoxide is generated from O2 in a cyanide-sensitive reaction involving a reduced component of complex III of the mitochondrial respiratory chain, particularly when antimycin A is present. Although it is generally believed that ubisemiquinone is the electron donor to O2, little experimental evidence supporting this view has been reported. Experiments with succinate as electron donor in the presence of antimycin A in intact rat heart mitochondria, which contain much superoxide dismutase but little catalase, showed that myxothiazol, which inhibits reduction of the Rieske iron-sulfur center, prevented formation of hydrogen peroxide, determined spectrophotometrically as the H2O2-peroxidase complex. Similarly, depletion of the mitochondria of their cytochrome c also inhibited formation of H2O2, which was restored by addition of cytochrome c. These observations indicate that factors preventing the formation of ubisemiquinone also prevent H2O2 formation. They also exclude ubiquinol, which remains reduced under these conditions, as the reductant of O2. Since cytochrome b also remains fully reduced when myxothiazol is added to succinate- and antimycin A-supplemented mitochondria, reduced cytochrome b may also be excluded as the reductant of O2. These observations, which are consistent with the Q-cycle reactions, by exclusion of other possibilities leave ubisemiquinone as the only reduced electron carrier in complex III capable of reducing O2 to O2−.
Background: Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor a has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described. Methods: Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects. Results: Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.
Endophenotypes are proposed to occupy an intermediate position in the pathway between genotype and phenotype in genetically complex disorders such as depression. To be considered an endophenotype, a construct must meet a set of criteria proposed by Gottesman and Gould (2003). In this qualitative review, we summarize evidence for each criterion for several putative endophenotypes for depression: neuroticism, morning cortisol, frontal asymmetry of cortical electrical activity, reward learning, and biases of attention and memory. Our review indicates that while there is strong support for some depression endophenotypes, other putative endophenotypes lack data or have inconsistent findings for core criteria.
Mitochondrial dysfunction in adipose tissue may contribute to obesity-related metabolic derangements such as type 2 diabetes mellitus (T2DM). Because mitochondria are a target for melatonin action, the goal of present study was to investigate the effects of melatonin on mitochondrial function in white (WAT) and beige inguinal adipose tissue of Zücker diabetic fatty (ZDF) rats, a model of obesity-related T2DM. In this experimental model melatonin reduces obesity and improves the metabolic profile. At 6 weeks of age, ZDF rats and lean littermates (ZL) were subdivided into two groups, each composed of four rats: control (C-ZDF and C-ZL) and treated with oral melatonin in the drinking water (10 mg/kg/day) for 6 weeks (M-ZDF and M-ZL). After the treatment period, animals were sacrificed, tissues dissected and mitochondrial function assessed in isolated organelles. Melatonin increased the respiratory control ratio (RCR) in mitochondria from white fat of both lean (by 26.5%, p <0.01) and obese (by 34.5%, p <0.01) rats mainly through a reduction of proton leaking component of respiration (state 4) (28% decrease in ZL, p <0.01 and 35% in ZDF, p <0.01). However, melatonin treatment lowered the RCR in beige mitochondria of both lean (by 7%, p < 0.05) and obese (by 13%, p < 0.05) rats by maintaining high rates of uncoupled respiration. Melatonin also lowered mitochondrial oxidative status by reducing nitrite levels and by increasing superoxide dismutase activity. Moreover, melatonin treatment also caused a profound inhibition of Ca-induced opening of mPTP in isolated mitochondria from both types of fat, white and beige, in both lean and obese rats. These results demonstrate that chronic oral melatonin improves mitochondrial respiration, and reduces the oxidative status and susceptibility to apoptosis in white and beige adipocytes. These melatonin effects help to prevent mitochondrial dysfunction and thereby to improve obesity-related metabolic disorders such as diabetes and dyslipidemia of ZDF rats. This article is protected by copyright. All rights reserved.