Mitochondrial Dynamics in the Regulation
of Nutrient Utilization and Energy Expenditure
Marc Liesa1and Orian S. Shirihai1,2,*
Medicine, 650 Albany Street, Boston, MA 02118, USA
2Department of Clinical Biochemistry, School of Medicine, Ben Gurion University, Beer-Sheva 84103, Israel
quality control might not be the only task carried out by mitochondrial dynamics. Recent studies link mito-
chondrial architecture as a mechanism for bioenergetic adaptation to metabolic demands. By favoring either
connected or fragmented architectures, mitochondrial dynamics regulates bioenergetic efficiency and
energy expenditure. Placement of bioenergetic adaptation and quality control as competing tasks of mito-
chondrial dynamics might provide a new mechanism, linking excess nutrient environment to progressive
mitochondrial dysfunction, common to age-related diseases.
As our relationship with mitochondria evolves, we remain fasci-
conditions: aging and metabolic diseases. While aging involves
insufficiency of mitochondrial quality control and turnover mech-
anisms (such as autophagy), type 2 diabetes and obesity are
influenced by the ability of the organism to deal with excess
nutrient environment. The observation that both conditions are
impactedbythe durationof exposureto excessnutrient environ-
ment raises the question, are the tasks of handling nutrients in
excess and maintaining quality control ever in conflict? In this
review, we discuss evidence to support a hypothesis that adap-
tation to excess nutrient environment interferes with quality
control functions and, as a result, affects mitochondrial function
in a magnitude that reflects the duration to which the organism
was exposed to excess nutrient environment.
In response to changes in energy demand and supply, the
organism adapts by adjusting both its capacity and/or efficiency
of ATP production. Mitochondrial bioenergetic efficiency is
defined as the ATP produced in the mitochondria per molecule
of nutrient (Figure 1), and mitochondrial ATP synthesis capacity
is defined as the rate at which ATP is produced per unit of time.
As an adaptation to excess nutrients, the organism recruits
mechanisms to utilize nutrients first by storage and then by
waste (heat generation). While spending time at the gym may
be the appropriate way to waste energy and keep healthy,
reducing bioenergetic efficiency might enable energy waste in
tissues other than muscle and in individuals that are less
compatible with the gym.
Studies in the field of mitochondrial dynamics have identified
an intriguing link between energy demand and supply balance
and mitochondrial architecture. Cells exposed to a rich-nutrient
environment tend to keep their mitochondria in a separated
(fragmented) state, and mitochondria in cells under starvation
tend to remain for a longer duration in the connected (elongated)
state (Molina et al., 2009; Gomes et al., 2011). Thus, it appears
that bioenergetic adaptation that involves changes to bioener-
getic efficiency and mitochondrial ATP synthesis capacity also
implies remodeling of mitochondrial architecture.
However, bioenergetic adaptation is not the only mitochon-
drial task that involves changes to mitochondrial architecture.
A vital task that engages the fusion and fission machinery is
the mitochondrial life cycle (Twig et al., 2008a). The mitochon-
drial life cycle represents continuous changes to mitochondrial
architecture through fusion and fission events. These brief tran-
sitions between connected and separated mitochondria enable
tion of damaged material, thereby maintaining a healthy mito-
chondrial population. One can appreciate that the life cycle of
mitochondria would be compromised if mitochondrial fusion or
fore, under certain nutrient environments, bioenergetic adapta-
tion and quality control might represent conflicting tasks.
That mitochondrial quality control has evolved within the same
mechanism that controls for bioenergetic efficiency is not
surprising, given the understanding that a low-nutrient environ-
ment (caloric restriction) may support increased longevity.
Adaptation of bioenergetic efficiency and ATP synthesis
capacity to nutrient availability differs among tissues and is inti-
mately linked to their specific physiology. Thus, we will focus on
three paradigmatic tissues that show different bioenergetic effi-
ciencies and mechanisms of adaptation to nutrient availability:
(1) Brown adipose tissue: When stimulated, brown adipo-
cytes can go through an acute and robust transition
from high to low bioenergetic efficiency. Under these
stimulatory conditions, energy obtained from mitochon-
drial nutrient oxidation is almost entirely directed toward
heat production rather than ATP synthesis (reviewed in
Cannon and Nedergaard, 2004).
(2) Muscle: Muscle cells harbor higher bioenergetic effi-
ciency as compared to either beta cells (Affourtit and
Brand, 2006) or stimulated brown fat. In the contracting
red muscle, nutrient oxidation is primarily directed
Cell Metabolism 17, April 2, 2013 ª2013 Elsevier Inc.
towards production of ATP in the mitochondria (Chappell
and Perry, 1954) to support contraction. Thus, the oxida-
tive muscle is a good example of high mitochondrial ATP
synthesis capacity and likely high bioenergetic efficiency
(Marcinek et al., 2004).
(3) Beta cells: Mitochondria in pancreatic beta cells serve as
nutrient sensors and signal generators for insulin secre-
tion. Nutrients are ‘‘sensed’’ through their metabolism,
which involves nutrient oxidation mediated by beta cell
mitochondria (Ashcroft et al., 1984; reviewed in Deeney
et al., 2000). Therefore, bioenergetic efficiency is ex-
pected to be highly regulated to allow proper insulin
Although the mechanisms for tissue-specific differences in
bioenergetic efficiency are understood to a certain extent, less
is known about the contribution of mitochondrial dynamics to
tissue and diet-dependent bioenergetic efficiency and mito-
chondrial ATP synthesis capacity. Mitochondrial dynamics is
a concept that comprises mitochondrial architecture resulting
from movement, tethering, fusion, and fission events. Multiple
important for cell viability, senescence, mitochondria health,
bioenergetic function, quality control, and intracellular signaling
(reviewed in Liesa et al., 2009; reviewed in Twig et al., 2008b).
On the other hand, we are now beginning to understand how
nutrients and the cellular metabolic state are regulating mito-
chondrial dynamics in different tissues and vice versa, particu-
larly in the beta cell, brown adipose tissue, and muscle (Molina
et al., 2009; Quiro ´s et al., 2012; Sebastia ´n et al., 2012). Along
with this, the relevance of mitochondrial dynamics in the specific
physiology of different tissues has only been revealed recently,
mostly thanks to different mouse models harboring tissue-
specific deletions of core components regulating mitochondrial
dynamics (Chen et al., 2007, 2010; Chen et al., 2011; Ishihara
et al., 2009; Sebastia ´n et al., 2012; Wakabayashi et al., 2009;
Zhang et al., 2011).
In this context, the aim of this review is to summarize the
current understanding of mitochondrial bioenergetic function
and efficiency regulation by nutrient availability and energy
demand in health and disease. We will discuss how mitochon-
drial dynamics may be required for proper adaptation to the
diverse bioenergetic requirements. In the last section, we will
provide a model in which adaptation to sustained exposure to
nutrient excess results in prolonged changes to mitochondrial
dynamics. These changes can impact mitochondrial quality
control and thereby contribute to the mitochondrial dysfunction
characteristic of metabolic and other age-related diseases.
Regulation of Cellular Bioenergetics by Nutrients
How Can Bioenergetic Efficiency Affect Cellular
Functionality and Viability?
Intuitively, it is expected that conditions of limited nutrient avail-
ability will increase the ratio of ATP produced per nutrient
consumed, thereby reducing and optimizing the consumption
of nutrients. Mechanisms to increase energy efficiency are ex-
pected to diverse between tissues that are primarily relying on
‘‘anaerobic’’ glycolysis and those that are relying primarily on
oxidative metabolism for the production of ATP.
In this regard, recent studies performed in transformed cell
lines demonstrate that starvation increases mitochondrial ATP
synthesis capacity (ATP production per unit of time). This
increase involves the formation of ATP synthase dimers at the
cristae curvatures, which show higher activity (Gomes et al.,
2011). This result may represent a shift from ‘‘anaerobic’’
glycolysis (to lactate) toward mitochondrial respiration under
starvation, as respiration can produce more ATP per molecule
of glucose. In oxidative cell types, one would also expect the
activation of mechanisms that increase mitochondrial bioen-
ergetic efficiency to ensure survival under limited availability of
nutrients. Mechanisms enhancing mitochondrial bioenergetic
efficiency have not been described in detail under these condi-
tions. On the other hand, increased mitochondrial ATP synthesis
capacity reported in transformed cell lines (Gomes et al., 2011)
was associated with and dependent on changes in mitochon-
drialdynamics, whichwere presented asdecreased fissionrates
and mitochondrial elongation. This change in dynamics
suggests that elongation could be an active mechanism contrib-
uting to increased mitochondrial bioenergetic efficiency.
energy obtained from nutrient oxidation toward heat production,
most commonly by increased uncoupled respiration. Decreased
bioenergetic efficiency may serve as a protective mechanism
from the detrimental effects associated with nutrient overload.
This is achieved through the reduction of reactive oxygen
species (ROS) production and by the enhanced removal of
excess nutrients and their potentially cytotoxic metabolites
Balanced nutrient availability
Figure 1. Regulation of Cellular Bioenergetic Efficiency under
Conditions of Nutrient Excess
In the balanced statefuel/nutrient ‘‘supply’’is sufficientto sustain energy (ATP)
‘‘demand.’’ Under this condition, ‘‘waste’’ or inefficiency in the form of heat is
minor. Nutrient excess, characterized by ‘‘excessive supply’’ in the absence of
a parallel increase in ‘‘demand,’’ represents a situation in which the energy
required to satisfy ATP demand is lower than the available energy. This is
compensated for by addition of an energy sink that does not involve ATP
synthesis. This component is inefficiency/waste in the form of heat. The major
mechanism for inefficiency/waste in the form of heat is mitochondrial proton
‘‘leak.’’ This mechanism can slow down nutrient accumulation and prevent the
Cell Metabolism 17, April 2, 2013 ª2013 Elsevier Inc.
The flow of electron-mediated proton translocation in the
respiratory chain can be compared to a flow of water in a garden
hose (see the ‘‘Understanding Mechanisms of Bioenergetic Effi-
ciency and Changes in ATP Synthesis Capacity by Respiration
Studies’’ section for a more detailed bioenergetics description).
NADH, resulting from nutrient oxidation, feeds the hose inlet with
water, while ATP synthase controls the hose final outlet. The
pressure that the flow of water generates in the hose is the mito-
chondrialmembrane potential(Dcm). Theflowof waterandpres-
sure in the hose are determined by the rates of NADH production
and ATP synthesis. The minimum and maximum values of pres-
sure that the hose can hold are determined by the material and
integrity of the hose, not by the flow of water or the inlets and
outlets (i.e., the range of Dcmin mV is determined by thermody-
namics and theintegrity of the organelle). ATP synthesisis deter-
mined by ATP demand, meaning that the hose outlet is
sure, we would not have to be concerned with any parameter
beyond ATP demand. However, this is not the case. The hose,
as it turns out, has some cuts through which water can escape,
whenpressurebuilds up. Apressurevalve thatcan divert excess
waterthroughasafeconduit can reducethe pressureinthehose
and prevent water leakage through the ‘‘cuts’’ in the hose
(increasing or maintaining the flow of water). In our analogy,
the escape of water through the cuts represents the escape of
electrons to produce ROS. The pressure valve represents the
combination of inducible and inherent uncoupled respiration,
the latter being caused by the inherent proton leak of the inner
membrane. Inducible uncoupling can include uncoupling protein
1 (UCP1) activation in brown fat and the permeability transition
pore opening. Inherent, nonactivated, proton leak is directly
(but nonlinearly) correlated to the membrane potential and is
mediated, in part, by inner membrane proteins (such as adenine
nucleotide translocator or nonactivated UCP1 in brown fat)
(Parker et al., 2009). The balance between ATP demand and
nutrient supply determines both the rate of ATP synthesis and
the level of ROS produced by mitochondria.
Different tissues employ different mechanisms in their
response to nutrient overload. The selection of specific compen-
satory mechanisms allows each tissue to maintain its unique
primary function, while minimizing side effects related to ROS
production. In certain cell types, compensatory mechanisms
are placed upstream of the mitochondria, preventing their expo-
sure to high levels of fuel. However, in beta cells, brown adipose
tissue, and muscle, mounting evidence suggests that conditions
of nutrient excess that increase fuel availability to the mitochon-
dria might modulate bioenergetic efficiency and mitochondrial
ATP synthesis capacity (Koves et al., 2008; Bonnard et al.,
2008; Rothwell and Stock, 1979; Wikstrom et al., 2007).
Understanding Mechanisms of Bioenergetic Efficiency
and Changes in ATP Synthesis Capacity by Respiration
Mitochondria from any tissue can provide energy in the form of
ATP as a result of nutrient oxidation (Chance and Williams,
1955; Mitchell, 1961). Oxidation of nutrients will provide elec-
trons to the mitochondrial electron transport chain (constituted
tial transport of electrons from complex I or II to III and IV
extrudes protons from the matrix to the intermembrane space,
generating an electrochemical gradient (DmH+) resulting in
a difference in charge (Dc) and in proton concentration (DpH).
utor to DmH+(reviewed in Nicholls and Ferguson, 2002). In intact
mitochondria, maximal and minimal Dcmvalues are around 225
and 90 mV, respectively. This range in mV is dictated by the
thermodynamic stability of functional mitochondria and repre-
sents the balance between proton extrusion and re-entry.
Energy from proton re-entry through complex V is used for the
synthesis of ATP from ADP. The state at which isolated mito-
chondria are synthesizing ATP at maximal rates is named state
3 (Chance and Williams, 1955), and it occurs at intermediate
Dcmvalues (?140 mV). As such, this state is characterized by
a high rate of both proton extrusion and re-entry (reviewed in
Nicholls and Ferguson, 2002).
Proton re-entry through mechanisms that do not involve
complex V and ATP synthesis are referred to as uncoupled
respiration. Uncoupled respiration results in the generation of
heat and is not controlled by ATP turnover (reviewed in Nicholls
and Ferguson, 2002). It is important to distinguish between two
different types of respiratory states resulting from uncoupling.
These two respiratory states determined in isolated mitochon-
dria show major functional differences and might mimic respira-
tory states under different physiological conditions in vivo:
(1) Respiration controlled by inherent proton leak. This is
typically measured in vitro, in isolated mitochondria in
which ATP synthesis has been inhibited either by ADP
exhaustion (state 4) or by the use of complex V inhibitor
olygomycin. It is also referred to as respiration controlled
by basal proton conductance (Parker et al., 2009) and can
mimic physiological conditions of decreased mitochon-
drial ATP demand and high nutrient availability.
(2) Respiration controlled by inducible uncouplers. This type
of uncoupled respiration can be experimentally mimicked
molecules located in the inner mitochondrial membrane,
such as UCP1. The activation of these endogenous
uncouplers takes the control of respiration from ATP
controlled by the capacity of the respiratory chain and
by the availability of mitochondrial fuels. This type of
respiration is also characterized by decreases Dcm
values, due to increased proton re-entry. Itis also referred
to as inducible proton conductance (Parker et al., 2009).
A key difference between these two types of uncoupled respi-
ration is the membrane potential at which they are conducted.
Mitochondrial respiration controlled by inherent proton leak,
which occurs in coupled mitochondria under conditions of low
ATP synthesis and high nutrient availability, is associated with
The high Dcmvalues result from a combination of decreased
rates of proton re-entry through ATP synthase and low values
of proton conductance contributed by the inherent proton leak.
The combination of these effects maintains Dcmvalues within
the range dictated by thermodynamic stability of intact mito-
chondria. This state is associated with relatively higher ROS
generation, as a consequence of the increase in Dcm.
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Cell Metabolism 17, April 2, 2013 ª2013 Elsevier Inc.