J Physiol 599.

3 (2021) pp 803–817 803

SYMPOSIUM REVIEW

Exercise and mitochondrial health

Jonathan M. Memme1,2 , Avigail T. Erlich1,2 , Geetika Phukan1,2 and David A. Hood1,2
1
Muscle Health Research Centre, York University, Toronto, Ontario, Canada, M3J 1P3
2
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada, M3J 1P3

Edited by: Scott Powers & Karyn Hamilton

The Journal of Physiology

Abstract Mitochondrial health is an important mediator of cellular function across a range of

tissues, and as a result contributes to whole-body vitality in health and disease. Our under-
standing of the regulation and function of these organelles is of great interest to scientists
and clinicians across many disciplines within our healthcare system. Skeletal muscle is a useful
model tissue for the study of mitochondrial adaptations because of its mass and contribution to
whole body metabolism. The remarkable plasticity of mitochondria allows them to adjust their

Jonathan M. Memme is a PhD candidate and recipient of the Natural

Sciences and Engineering Research Council of Canada (NSERC) Canada
Graduate Scholarship-Doctoral. His research explores the molecular
signals regulating muscle mitochondrial quality control with exercise and
disuse. Avigail T. Erlich is a PhD student and recipient of the Ontario
Graduate Scholarship, investigating mitochondrial turnover and
lysosomal biogenesis in muscle. Geetika Phukan is a postdoctoral fellow
with research focused on mitochondria in Alzheimer’s disease and muscle
chronic contractile activity. David A. Hood is a NSERC Canada Research
Chair in Cell Physiology, Professor in the School of Kinesiology and Health
Science, and the Director of the Muscle Health Research Centre at York
University. His research is devoted to studying mitochondrial biogenesis
and turnover in health and disease in mammalian skeletal and cardiac
muscles with exercise, disuse and ageing. All authors are members of the
Muscle Health Research Centre at York University.

This review was presented at the 2018 ACSM “Integrative Physiology of Exercise (IPE)” conference, which took place at Sheraton San Diego Hotel
and Marina, San Diego, California, 5–8 September 2018.


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804 J. M. Memme and others J Physiol 599.3

volume, structure and capacity under conditions such as exercise, which is useful or improving
metabolic health in individuals with various diseases and/or advancing age. Mitochondria exist
within muscle as a functional reticulum which is maintained by dynamic processes of biogenesis
and fusion, and is balanced by opposing processes of fission and mitophagy. The sophisticated
coordination of these events is incompletely understood, but is imperative for organelle function
and essential for the maintenance of an interconnected organelle network that is finely tuned
to the metabolic needs of the cell. Further elucidation of the mechanisms of mitochondrial
turnover in muscle could offer potential therapeutic targets for the advancement of health and
longevity among our ageing populations. As well, investigating exercise modalities that are both
convenient and capable of inducing robust mitochondrial adaptations are useful in fostering
more widespread global adherence. To this point, exercise remains the most potent behavioural
therapeutic approach for the improvement of mitochondrial health, not only in muscle, but
potentially also in other tissues.

(Received 21 August 2019; accepted after revision 28 October 2019; first published online 1 November 2019)
Corresponding author David A. Hood: Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, ON, M3J 1P3, Canada. Email: dhood@yorku.ca

Abstract figure legend The mitochondrial life cycle is regulated by the finely tuned balance of biogenesis and fusion,
opposed to fission and mitophagy. At any moment these processes are in a state of flux and are induced and/or
suppressed depending on the status of the cell and the physiological conditions it is subjected to. A hallmark feature
of aged muscle is the reduction of both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial fractions,
determined by a thinner SS mitochondria layer (yellow arrow) and fragmented IMF pool, as compared to their
younger counterparts. Additionally, aged muscle presents an accumulation of damaged mitochondria (green organelles).
Physical activity is a well-established inducer of mitochondrial remodelling that promotes increases in both SS layer
thickness as well as IMF interconnectivity. Additionally, aged muscle is capable of adapting to the exercise stimulus
which improves mitochondrial content and quality. Indications of a mitochondrial contribution to sarcopenia suggest
that, with regular exercise, mitochondrial health can be preserved well into old age and contribute to whole body
vitality.

Introduction to mitochondrial health
Mitochondria are unique organelles that are derived from
prokaryotic cells that long ago fused with a host cell. They
are imperative for the provision of energy-rich ATP and
the regulation of cellular longevity across multiple organ
systems. Colloquially termed ‘the powerhouses of the
cell’, this unofficial moniker is an underrepresentation
of the variety of functions these mighty organelles
play. However, the fact that mitochondria are widely
recognizable beyond the science community is indicative
of their relative importance as integral organelles in
virtually all cells throughout the body. Moreover, the
volume of mitochondrial research within the medical
sciences community is steadily on the rise. Over the
past two decades mitochondrial-related publications
have continued to increase beyond the rate of all other
cellular organelles, possibly as a result of the recognition
of the convergence of essential signalling pathways and
biological processes on mitochondria (Picard et al.
2016).
Mitochondria are capable of adapting to altered
metabolic demands. Through processes of biogenesis
and fusion, newly formed mitochondria are adjoined to
neighbouring organelles to increase their capacity for ATP
synthesis, the sharing of metabolites, and Ca2+ handling
(Spinelli & Haigis, 2018). Conversely, where mitochondria
are overabundant and/or dysfunctional, processes of
fission and mitochondrial clearance (mitophagy) occur
to re-establish metabolic homeostasis and maintain
mitochondrial health within the cells (Hood et al.
2019). At any moment these opposing processes are
in a state of flux, depending on the metabolic needs
of the tissue, to calibrate and promote an optimal
mitochondrial pool. When the cell is subjected to
conditions that perturb metabolic homeostasis, such as
exercise or advancing age, this balance in mitochondrial
regulation can shift toward an increase in synthesis and
fusion, or fission and mitophagy, respectively (Mishra &
Chan, 2016). The classic mechanism of mitochondrial
fusion is achieved through the activity of the proteins
mitofusin-1/2 (Mfn1/2) and optical atrophy protein
1/2 (Opa1/2) which facilitate fusion of adjacent outer
and inner membranes, respectively, thus establishing an
expanded organelle network (Mishra & Chan, 2016).
Conversely, mitochondrial fission is accomplished by the
joint action of proteins dynamin related protein 1 (Drp1),
mitochondrial fission factor (Mff) and fission protein 1
(Fis1), the actions of which culminate in the constriction


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J Physiol 599.3
and cleavage of organelle fragments from the network to
allow for proper clearance (Losón et al. 2013; Toyama et al.
2016).
Recent research has uncovered the complexity of
mitochondrial morphology, exhibited by connections
through either electron dense intermitochondrial
junctions (IMJs), as well as membranous protrusions
termed nanotunnels (Glancy et al. 2017; Vincent et al.
2017). It is proposed that IMJs allow for electrical
coupling of the mitochondrial pool, as well as the
ability to rapidly segregate dysfunctional organelles
from the reticulum, while simultaneously allowing for
either the repair or removal of the malfunctioning
organelle (Glancy et al. 2017). In contrast, nanotunnels
promote the sharing of mtDNA, proteins, metabolites
and other small molecules to non-adjacent mitochondria
(Vincent et al. 2017). These small (40–200 nm diameter)
double-membrane extensions appear to exist primarily
to connect mitochondria in tissues with restricted
mitochondrial motility (Vincent et al. 2019, 2019).
Nanotunnels may develop as a compensatory mechanism
of mitochondrial crosstalk under stress conditions, when
more direct mitochondrial communication is not possible
(Vincent et al. 2019, 2019).
Mitochondrial morphology and function also differ
across tissues, in order to match the specialized
metabolic demand of their respective cells, or the
changing pathological or physiological conditions
that they are subjected to (Fernández-Vizarra et al.
2011). Skeletal muscle provides an excellent tissue to
investigate the various morphological configurations
of mitochondria within a cell. When viewed using
electron microscopy (EM), mitochondria within muscle
have distinct geographical subpopulations (Kayar et al.
1988; Cogswell et al. 1993). Below the sarcolemmal
membrane reside the subsarcolemmal (SS) mitochondria
which present the more classic rounded appearance.
They specialize in providing ATP for nuclear gene
transcription and membrane transport (Kirkwood et al.
1986; Ogata & Yamasaki, 1997). Interspersed throughout
the contractile myofibrillar protein network are the
intermyofibrillar (IMF) mitochondria, which are more
elongated and interconnected (Kirkwood et al. 1986;
Ogata & Yamasaki, 1997). These mitochondria provide
ATP for muscle contraction and they are tightly connected
to the sarcoplasmic reticulum (SR). Thus, these may
additionally play a prominent role in Ca2+ signalling
(Ogata & Yamasaki, 1997; Boncompagni et al. 2009).
In response to whole-body exercise, skeletal muscle
mitochondria increase their rates of ATP synthesis to
match the metabolic demands of the cell. Coincidentally,
a myriad of signalling events converge to activate nuclear
and cytoplasmic proteins to orchestrate the initiation
of biogenesis, as well as mitophagy of a pre-existing,
unhealthy mitochondrial pool.

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Exercise and mitochondrial health 805
Signalling involved in mitochondrial
biogenesis
As mammalian mitochondria are derived from symbiotic
ancestors, they maintain their own individual 16.5-kb
genome which works in conjunction with nuclear
DNA for the expression of mitochondrial proteins
(Calvo et al. 2016). Of the nearly 1200 proteins that
make up mitochondria, mtDNA is responsible for
the transcription of just 13, albeit integral, electron
transport chain (ETC) proteins, along with 2 rRNAs
and 22 tRNAs (Anderson et al. 1981). Thus, the vast
majority (>99%) of the remaining mitochondrial
proteins require transcription in the nucleus and import
into their appropriate organellular compartments via
mitochondrial chaperones and protein import channels.
This unique biological interaction, requiring the finely
tuned coordination of both mtDNA and nDNA genomes
to regulate organelle abundance, has added considerable
fascination, and complexity, to the understanding of
mitochondrial health, disease and turnover.
The nuclear transcription of mitochondrial proteins
is undoubtedly regulated by many proteins, but none
is more prominent in the literature than the trans-
criptional coactivator peroxisome proliferator activated
receptor γ coactivator 1α (PGC-1α), considered the
master regulator of mitochondrial biogenesis (Hood,
2001; Handschin & Spiegelman, 2006; Scarpulla, 2011;
Scarpulla et al. 2012). PGC-1α and its family members,
PGC-1β and PGC-related co-activator (PRC), upregulate
gene transcription by docking with transcription factors
(TFs) and additional proteins on DNA promoters to
regulate nuclear genes encoding mitochondrial proteins
(NuGEMPs) (Puigserver et al. 1999; Scarpulla, 2011;
Scarpulla et al. 2012). Acute exercise initiates a
multitude of signals that converge on PGC-1α, with
the most widely accepted signals being: (i) activation of
calcium/calmodulin-dependent protein kinase (CaMK),
through the increased intracellular Ca2+ concentration
(Ojuka et al. 2003); (ii) activation of p38 mitogen-activated
protein kinase (p38 MAPK), which is sensitive to multiple
stressors such as reactive oxygen species (ROS) (Puigserver
et al. 2001; Akimoto, 2005; Hood, 2009; Irrcher et al.
2009; Ristow et al. 2009); and (iii) AMP-activated protein
kinase (AMPK) phosphorylation, activated by the hydro-
lysis of ATP by myosin ATPases and the resultant increase
in AMP:ATP ratio (Winder et al. 2000; Irrcher et al.
2009). Additionally, cAMP is another activator of PGC-1α
expression which may be induced through adrenergic
signalling (Handschin et al. 2003; Fig. 1). Once activated,
PGC-1α can then interact with a variety of TFs, such
as nuclear respiratory factor (NRF)-1/2, which induce
the expression of mitochondrial transcription factor A
(Tfam). Tfam is subsequently imported into the organelle
and serves as the most important TF to upregulate the
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transcription of mtDNA-derived proteins (Gordon et al.
2001; Scarpulla, 2011). As such, this sequence of events
plays an important role in matching the expression of
mitochondrially encoded genes to the changing expression
of the nuclear genome. This transcriptional coordination
is important, as any imbalance between the expression
levels of either genome can lead to a disruption in
proteostasis within the organelle, and trigger a series of
mitochondrial retrograde signals to the nucleus involving
the mitochondrial unfolded protein response (UPRmt ) as
an attempt to maintain a proper, functional proteome.
Further retrograde signalling can originate
post-transcriptionally at the level of protein import.
Nuclear-encoded mitochondrial proteins contain
a mitochondrial targeting sequence (MTS) that is
recognized by cytosolic chaperones. These chaperones are
responsible for unfolding their cargo and delivering the
protein to the mitochondrial protein import machinery
(PIM), comprising the translocases of the outer and inner
membranes (TOM and TIM, respectively) (Bolender et al.
2008; Chacinska et al. 2009). A matrix-targeted protein
enters the mitochondria through the TOM complex
and then subsequently through the TIM complex,
before reaching its final destination within the organelle
(Chacinska et al. 2009). In the matrix, the MTS is cleaved
by the mitochondrial processing peptidase (MPP) and
the protein is refolded to its mature conformation by
mitochondrial chaperones, such as mtHSP70, HSP60 or
CPN10, and may be incorporated with other nuclear-
or mitochondrially encoded proteins to form functional
complexes (Harbauer et al. 2014; Fig. 1). However,
disruptions in mitochondrial protein import can arise
as a result of nuclear/mitochondrial imbalances. When
the cell is under stress, such as during development
or with exercise, protein import is accelerated and the
UPRmt is activated through the upregulation of HSP60
and CPN10 to ensure that the accumulated unfolded
proteins achieve their mature configuration (Memme
et al. 2016; Mesbah Moosavi & Hood, 2017; Oliveira
& Hood, 2018). Additionally, increased expression of
mitochondrial proteases lon peptidase (LonP) and
caseinolytic mitochondrial matrix peptidase proteolytic
subunit (ClpP) degrade misfolded proteins to alleviate
their proteotoxic burden (Mottis et al. 2014).
The trigger that initiates the upregulation of these
chaperones may be ROS. ROS activate the stress
kinase, general control nonderepressible 2 (GCN2).
Activated GCN2 phosphorylates the eukaryotic initiation
factor alpha (eIF2α), subsequently decreasing global
protein synthesis, thus reducing the level of nascent
proteins that require import and assembly within
the mitochondria (Shenton et al. 2006; Baker et al.
2012). While phosphorylated eIF2α decreases general
protein translation, it selectively increases translation of
proteins containing an uORF in the 5ʹ UTR, such as
CCAAT/enhancer-binding protein (C/EBP) homologous
protein (CHOP), and the activating transcription factors
4 and 5 (ATF4 and ATF5) to upregulate the expression
of mitochondrial chaperones and proteases (Fiorese et al.
2016; Melber & Haynes, 2018). Proteolytic cleavage of
misfolded proteins also generates peptide fragments that
directly suppress organellular import capacity (Fig. 1).

Figure 1. Regulation of mitochondrial health with exercise and the influence of age
Exercise induces robust changes in mitochondrial content and quality that are beneficial for metabolic health. A,
motor unit recruitment of myofibres produces action potentials that induce Ca2+ release from the SR. Increased
cytosolic Ca2+ prompts myosin-actin interactions, crossbridge cycling, and the hydrolysis of ATP to produce muscle
force, as well as the generation of ATP and ROS from respiring mitochondria. B, consequently, these events activate
the signalling kinases that converge on PGC-1α, allowing its translocation to the nucleus where it coactivates TFs
to increase the expression of NuGEMPS, such as the mtDNA transcription factor, Tfam. C, newly expressed
nuclear-derived proteins are then imported into mitochondria through translocases of the outer, and then inner
membranes (TOM and TIM, respectively). D, the exercise stimulus increases protein levels within mitochondria,
which promotes the activation of the UPRmt . The cleavage of terminally misfolded protein aggregates in the matrix
and the release of their peptide fragments, block ATF5 mitochondrial entry, thus redirecting it to the nucleus to
upregulate transcription of mitochondrial chaperones and proteases and equip the organelle with an augmented
capacity for protein folding. E, mitochondrial fusion proteins Mfn1/2 along with Opa1 facilitate the fusion of the
outer and inner membranes, respectively, allowing for improved sharing of metabolites amongst neighbouring
organelles. F, regions of the mitochondrial network may become dysfunctional as they are incapable of matching
the metabolic needs of the tissue and require segregation from the reticulum in order to spare their adjacent
organelles from further impairment. These damaged organelles undergo fission, mediated by the interaction of
proteins Fis1 and Mff with Drp1 to constrict and remove the organelles, allowing for their clearance via mitophagy.
G, once separated, dysfunctional mitochondria with a low  accumulate PINK1 on their outer membrane. PINK1
recruits the E3-ligase Parkin, which subsequently ubiquitinates outer membrane proteins to flag the organelle for
removal via mitophagy. The adapter protein p62 binds to the ubiquitin on the tagged cargo, as well as to LC3-II
embedded in the phagophore membrane, and promotes the formation of the autophagosome, which fuses
with the lysosome to degrade the mitochondria and release the constituent amino acids for cellular recycling. H,
aged muscle displays attenuated PGC-1α signalling for mitochondrial biogenesis (red line), as well as increased
fission:fusion protein ratio (green line), thus promoting a fragmented network of organelles, as well as suppressed
mitophagy flux.


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808 J. M. Memme and others
This inhibition of import promotes a mechanistic switch
towards mitochondrial clearance through mitophagy via
stabilization of PTEN-induced putative kinase protein
1 (PINK1) on the outer membrane of dysfunctional
organelles (see below). Thus, the protein import process is
not only essential for the translocation of nuclear-derived
proteins into the organelle, it also serves to match the
health status of the organelle to the appropriate signalling
response in order to maintain an optimal mitochondrial
pool. Altogether, the UPRmt within skeletal muscle has
been shown to be important for the differentiation of
C2C12 myoblasts into mature myotubes, as well as in
the basal regulation of mitochondrial maintenance within
skeletal muscle in vivo (Mesbah Moosavi & Hood, 2017;
Oliveira & Hood, 2018).
The effect of various exercise training
modalities on mitochondria
It is now well recognized that exercise is a potent
stimulus to induce the signalling pathways described
above, which ultimately produce robust phenotypic
changes in the mitochondrial milieu and improve the
quantity and quality of the organelle network, leading
to greater muscle health. It was through John Holloszy’s
pioneering work that we first came to understand the
important training parameters that are required to achieve
a particular level of adaptation, and how exercise training
promotes mitochondrial biogenesis (Holloszy, 1967).
Favourable mitochondrial adaptations in muscle can
only be achieved if training is performed at a sufficient
frequency, intensity and duration, for an adequate length
of time (Holloszy, 1967). Since the 1960s, decades’ worth
of research has demonstrated that exercise promotes
a robust increase in mitochondrial content, as well
as improved oxidative phosphorylation and respiratory
capacity per mitochondrion (Burgomaster et al. 2008;
Jacobs & Lundby, 2013; Porter et al. 2015). Additionally,
chronic training reduces the production of ROS, indicative
of an enhanced capacity for electron flow through the
ETC (Holloway, 2017). Given that these adaptations are
favourable for improved muscle health, scientists have
continually strived to determine the precise signalling
pathways mediating mitochondrial quality control, which
includes the result of biogenesis and fusion, as opposed to
fission and mitophagy.
Since Hoppeler et al. (1973) described a correlation
between mitochondrial volume and V̇O2 peak , the
association of mitochondrial content within muscle and
exercise capacity has been a focal point for fitness and
exercise practitioners to harness modalities that improve
aerobic potential and performance. For many years, end-
urance training was considered the primary means of
achieving mitochondrial adaptations. Endurance exercise
training increases total mitochondrial proteins including
J Physiol 599.3
those involved in β-oxidation, the tricarboxylic acid (TCA)
cycle, and the electron transport chain, thus improving
the capacity for energy provision to the exercising muscle
(Holloszy & Booth, 1976). In fact, a single bout of end-
urance exercise is sufficient to induce structural changes
in the mitochondrial network that promote augmented
function of the organelle network (Picard et al. 2013). With
prolonged endurance training, mitochondrial volume
typically increases as much as 40–50% and this increase
in content is paralleled by more modest improvements in
respiration and oxidative capacity of the mitochondria on
a per organelle basis (Baldwin et al. 1972). Additionally,
mitochondrial adaptations to exercise vary across the
different fibre types, depending on the initial organelle
content, as well as the degree of motor unit recruitment
during the training session. In humans, slow-twitch (type
I) fibres contain the highest percentage of mitochondria,
followed by fast-twitch red (type IIa) fibres, and the whiter
type IIx fibres, respectively (Howald et al. 1985). With
training, the mitochondrial content within any of these
fibre types can be enhanced, indicating that mitochondrial
adaptations are not dependent on the myosin-based fibre
type per se, but instead are based on the stimulus and the
recruitment of that fibre (Lundby & Jacobs, 2016).
Terjung and colleagues illustrated the important inter-
play between intensity and duration in determining the
extent of mitochondrial adaptation in each fibre type
(Dudley et al. 1982). Type I fibres in particular are
most easily recruited at exercise intensities as low as
40% of V̇O2 max and lower. As workload increases and
exceeds 40% of V̇O2 max, type IIa fibres are recruited, and
only after the exercise intensity surpasses about 75% of
V̇O2 max will type IIx fibres be engaged (Sale, 1987). Based
on this principle – that motor units must be recruited
in order to adapt – training approaches have evolved
from the traditional long-distance endurance exercise to
alternative, time-saving modalities, such as sprint inter-
val training (SIT), high intensity interval training (HIIT)
and even resistance exercise, which can lead to diverse
mitochondrial adaptations in muscle.
Resistance exercise is typically associated with muscle
hypertrophy and improved force-generating capacity, as
opposed to fatigue resistance and improved aerobic energy
metabolism (Baar, 2006). Historically, the expansion of
muscle cell size via hypertrophy has been viewed as
‘diluting’ mitochondrial content in muscle and increasing
the diffusion distances (Lüthi et al. 1986). Indeed, a
recent review (Groennebaek & Vissing, 2017) of the
effect of resistance exercise has revealed the disparate
results obtained on mitochondria. However, it now
appears that resistance exercise has the potential of
inducing tangible improvements in maximal coupled
respiration measured in permeabilized myofibres, albeit
without a parallel increase in mitochondrial gene
expression or mitochondrial mass (Porter et al. 2015;

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J Physiol 599.3 Exercise and mitochondrial health
Groennebaek & Vissing, 2017). These adaptations may
be more pronounced in older individuals or in diseased
muscle such as sporadic inclusion body myositis, where
mitochondrial gene expression and, subsequently, content
is reduced in the basal state (Melov et al. 2007; Koo et al.
2019).
Interval training modalities such as HIIT and SIT have
gained considerable popularity of late, and are capable
of eliciting a similar level of adaptation as traditional
endurance training while doing so in considerably less
time, with a reduced exercise volume (MacInnis & Gibala,
2017). These exercise conditions involve the recruitment
of all motor units, and this contributes to the detection
of mitochondrial adaptations in all muscle fibres within
a mixed fibre biopsy sample (MacInnis & Gibala, 2017).
High intensity training bouts promote the activation of
the various signalling kinases that converge on PGC-1α to
promote organelle synthesis, as with endurance exercise
(Gibala et al. 2009; Little et al. 2011). However, exercise
at higher intensities generates more rapid ATP hydrolysis
and greater Ca2+ release to generate force. This should
lead to the enhanced activation of signalling kinases such
as p38 MAPK, AMPK and CaMKII, and could account for
the observations that repeated bouts of both HIIT and SIT
produce as much as 25–35% increases in mitochondrial
content in as few as 6–7 sessions (Gollnick et al. 1974; Egan
et al. 2010; MacInnis & Gibala, 2017).
Mitochondrial turnover and exercise
While the activation of the organelle biogenesis pathway
leads to an increase in mitochondrial content as
a result of training, it is also vital to eliminate
any mitochondrial segments that have outlived their
usefulness via mitophagy, in order to maintain or improve
the quality of the mitochondrial pool (Ljubicic et al. 2009;
Lira et al. 2013; Kim et al. 2018). Mitophagy occurs when
double-membraned vesicles, autophagosomes, engulf
damaged organelles that are flagged for degradation
by specialized proteins, when they exhibit a decreased
membrane potential and/or excessive increases in ROS
production (Wei et al. 2015; Kim & Hood, 2017; Kim
et al. 2018; Chen et al. 2018b; Triolo & Hood, 2019).
The main mitophagy pathway that has been investigated
in the context of exercise involves PINK1 and Parkin
(Fig. 1), two proteins that are well recognized for
their involvement, when mutated, in Parkinson’s disease
(Geisler et al. 2010; Matsuda et al. 2010; Lira et al.
2013; Wei et al. 2015). Normally, PINK1 is imported
into mitochondria and degraded by resident proteases.
However, if the mitochondrial membrane potential
dissipates, PINK1 accumulates on the outer membrane
as the protein import machinery loses its functionality
(Geisler et al. 2010; Matsuda et al. 2010; Wei et al. 2015).
The stabilization of PINK1 facilitates the recruitment of

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the E3-ubiquitin ligase Parkin to mitochondria, which
mediates the ubiquitination of various outer membrane
proteins such as Mfn2 and the voltage-dependent anion
channel (VDAC), tagging the organelle for degradation
(Geisler et al. 2010; Hood et al. 2011). The formation
of the autophagic vesicle, the phagophore, begins once
microtubule-associated protein 1 light chain 3 (LC3)-I
is lipidated into LC3-II with the aid of a collection
of autophagy-related gene products such as ATG7
(Tanida et al. 2004). The adapter protein p62/SQSTM1
contains both ubiquitin and LC3-II interacting domains,
and it serves as an anchor between the ubiquitinated
mitochondrion and the double-membraned phagophore,
thus facilitating organelle encapsulation and the formation
of the mature autophagosome (Geisler et al. 2010;
Matsuda et al. 2010; Kim & Hood, 2017; Chen et al.
2018a,b). The final stage of mitophagy requires the fusion
of the autophagosome with lysosomes for subsequent
breakdown by proteolytic enzymes within the lysosomal
lumen (Vainshtein & Hood, 2016). Therefore, lysosomal
health is extremely important for the maintenance of
mitochondrial quality in muscle.
The transcription factors that regulate lysosomal
biogenesis and function include the basic helix loop helix
(bHLH)-leucine zipper transcription factors TFEB and
TFE3. The overexpression of TFEB and TFE3 results in an
increased number of lysosomes and lysosomal enzymes
which serve to enhance catabolic activity (Settembre et al.
2013; Yang et al. 2018), while the depletion of these
proteins reduces the expression of lysosomal genes. In
addition to regulating lysosomal biogenesis, TFEB has also
been shown to be involved in regulating mitochondrial
biogenesis, and to coordinate the expression of genes
involved in autophagosome biogenesis and lysosome
fusion, indicated by an increased clearance of lipid droplets
and mitochondria with TFEB overexpression (Mansueto
et al. 2017).
Mitophagy is up-regulated by numerous cellular
stresses, including the energetic imbalance brought about
by acute exercise (Vainshtein & Hood, 2016; Erlich
et al. 2018; Chen et al. 2018b; Hood et al. 2019).
During exercise, the AMP/ATP ratio increases, thereby
activating AMPK and its downstream target Unc-51
like autophagy activating kinase 1 (ULK1). At the same
time mTORC1, a known suppressor of the process, is
inhibited (Kim et al. 2014; Tian et al. 2015; Laker et al.
2017). This sequence of initial steps has been shown to
activate mitophagy, as evident 6 h post-exercise using
the pMitoTimer reporter gene in vivo (Lira et al. 2013;
Laker et al. 2017) Other studies have shown that acute
exercise has a more rapid effect, by promoting Parkin
localization to mitochondria as well as an increase in
mitophagy flux, measured via LC3-II, p62 and ubiquitin
immediately post-exercise (Vainshtein et al. 2015; Chen
et al. 2018a,b). This appears to be regulated in part by
810 J. M. Memme and others
PGC-1α, since the exercise-induced increase in mitophagy
signalling and flux were not apparent in PGC-1α knockout
animals (Vainshtein et al. 2015). Acute exercise is also
capable of enhancing the activation and localization of
TFEB to the nucleus, possibly due to transient Ca2+
fluxes and subsequent calcineurin activation, which would
dephosphorylate TFEB and mediate its translocation
(Erlich et al. 2018). Therefore, exercise acts as a stimulus
for the induction of both PGC-1α and TFEB, which
act in concert to regulate both organelle biogenesis, as
well as mitophagy (i.e. turnover). Thus, these proteins
are critically involved in maintaining the health of the
mitochondrial pool within skeletal muscle.
In response to repeated bouts of exercise in the form of
endurance training, a number of studies have documented
increases in autophagy and mitophagy markers within
muscle (Lira et al. 2013; Ju et al. 2016). Chen et al.
(2018b) provided a direct measurement of mitophagy flux
utilizing colchicine treatment following a 6 week training
protocol. They found enhanced Parkin localization to the
mitochondria, as well as an increase in Parkin expression in
muscle of trained mice. Despite this, the exercise-induced
increase in mitophagy flux was reduced following training
(Lira et al. 2013; Chen et al. 2018b; Hood et al. 2019).
Other studies showed that mitophagy flux was reduced
in the basal state following a period of chronic contra-
ctile activity (CCA), an alternative model of endurance
training (Carter et al. 2018a; Leduc-Gaudet et al. 2019).
It is apparent from these studies, summarized elsewhere
(Guan et al. 2019), that the improvement in mitochondrial
function evident with these types of exercise reduced the
necessity for mitophagy signalling. In addition, chronic
exercise results in significant elevations in TFEB protein
as well as lysosomal markers Cathepsin D, mucolipin
(MCOLN1), and lysosomal associated membrane proteins
(LAMP) 1 and 2 (Kim & Hood, 2017; Mansueto et al.
2017; Kim et al. 2018). These results support the idea
that chronic exercise induces the expression of lysosomes
and autophagy-related genes which ensure that muscle
is primed to clear dysfunctional organelles, including
mitochondria, if their degradation is required. Given the
similar increases in mitochondrial content and function
observed in HIIT and SIT as compared to traditional
endurance training, it is reasonable to consider that
mitochondrial turnover would be induced to a similar
extent in these alternative training modalities. However,
little research has explored these relationships, and future
work in this area is warranted.
Is mitochondrial health maintained with
age?
A hallmark feature of ageing is the progressive loss of
muscle mass, termed sarcopenia, which develops from
structural and molecular changes occurring within the
J Physiol 599.3
tissue, and has extended implications on mobility, the
risk of falls, and the onset of type 2 diabetes and obesity
(López-Otı́n et al. 2013; Carter et al. 2015). Mitochondria
are culpable organelles in the progression of sarcopenia as
they are important regulators of a variety of factors that
contribute to the etiology of the condition, such as ATP
provision, oxidative stress, proteostasis, and apoptosis, as
well as inflammation and Ca2+ handling (Heber et al.
1996; Rapizzi et al. 2002; Kujoth et al. 2005; Schaap et al.
2006). The natural process of ageing along with prolonged
sedentarism promotes impairments in mitochondrial
integrity, further contributing to the progressive nature
of sarcopenia. Aged muscle can exhibit both fragmented
mitochondria, and/or atypically enlarged organelles when
viewed under EM (Iqbal et al. 2013; Leduc-Gaudet et al.
2015). Both SS and IMF fractions appear visibly thinner
and smaller within aged muscle compared to young
counterparts, and many studies have reported decreased
mitochondrial content with age (Short et al. 2003, 2005;
Chabi et al. 2008; Ljubicic et al. 2009; Iqbal et al. 2013).
This reduction is also paralleled by impaired protein
synthesis and respiration, and increased uncoupling
of O2 consumption to ATP synthesis contributing to
reduced maximal ATP reduction rate (MAPR) (Boffoli
et al. 1994; Rooyackers et al. 1996; Marcinek et al.
2005). The reasons for this decline at the cellular level
include reductions in the transcription of numerous genes
encoding mitochondrial enzymes, which are paralleled at
the protein level (Baraibar et al. 2013; Liu et al. 2013;
Carter et al. 2015). For example, at both the transcript
and protein level, proteins involved in organelle fission
and fusion are suppressed in muscle with age (Ibebunjo
et al. 2013). Additionally, there is an apparent shift in
the balance of these factors towards enhanced fission,
which agrees with the morphometric data suggesting a
fragmented network (Iqbal et al. 2013). As PGC-1α is
considered the master regulator of mitochondrial protein
expression, it is perhaps unsurprising that it, also, is
diminished at both the mRNA and protein level with
age, and this decreased expression probably contributes
to the reductions in mitochondrial volume that are
observed (Conley et al. 2007; Chabi et al. 2008; Koltai
et al. 2012; Fig. 1). PGC-1α levels are reduced in ageing
muscle as a consequence of decreased transcription of
the PGC-1α gene, possibly accompanied by enhanced
promoter methylation, and age-associated alterations
in the balance of regulatory transcription factors
which determine PGC-1α transcription (Carter et al.
2018b).
Another potential cause of mitochondrial dysfunction
that contributes to sarcopenia is the advancement of
mtDNA mutations that occurs with progressing age. In
fact, there is evidence to suggest that, where fibres harbour
mtDNA mutations in excess of 80%, there is a greater
indication of fibre breakage and atrophy (Wanagat et al.

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J Physiol 599.3 Exercise and mitochondrial health
2001; Bua et al. 2006). These mutations would give rise to
decrements in overall ETC function, which could in turn
contribute, in part, to the progressive atrophy observed in
adults after 50 years of age (Carter et al. 2015). However,
since other investigators have described no link between
mitochondrial COX deficiency and fibre atrophy (Rowan
et al. 2011), further work in this area seems to be required.
A central issue regarding mitochondrial health in ageing
muscle is whether the apparent decline in function and
content is a result of increasing levels of physical inactivity,
or a consequence of the ageing process per se. Previous
reviews have provided a more complete analysis of this
issue (Hood et al. 2016). What is clear is that regular
exercise can ameliorate at least a portion of the decline in
organelle health with age. However, this is accomplished
with reduced sensitivity to the exercise stimulus, as
signalling kinase activation is attenuated in muscle with
age, as is the ability to remove dysfunctional mitochondria
via exercise-induced mitophagy (Ljubicic & Hood, 2009;
Chen et al. 2018a). Resistance exercise may offer some
favourable advantages. Despite the reduced stimulus for
mitochondrial biogenesis that this mode of exercise creates
(see discussion above), it does stimulate muscle fibre
hypertrophy, and it prompts the recruitment and fusion of
satellite cells, which do not exhibit the mtDNA mutations
that are found in mature muscle fibres (Taivassalo, 1999;
Kowald & Kirkwood, 2014; Carter et al. 2015).
Aberrant mitophagy is also observed in sarcopenic
tissue (Fig. 1), which both exacerbates the dysfunction
of the reticulum contributing to advanced atrophy and
also explains the formation of abnormally enlarged
mitochondria when viewed under electron micro-
scope. However, the question of whether the increased
rates of mitophagy that occur in aged tissue are pro-
or maladaptive remains, since mitochondria remain
dysfunctional despite measured elevations in mitophagy
flux (O’Leary et al. 2013; Carter et al. 2018a; Chen et al.
2018a). A final consequence of inadequate organelle
recycling is the overproduction of ROS leading to the
subsequent activation of apoptosis. Indeed, in aged tissue
ROS are elevated along with reduced Ca2+ retention.
This promotes the mitochondrial release of pro-apoptotic
factors and subsequent DNA fragmentation, ultimately
promoting regional atrophy along the myofibre (Bua
et al. 2002; Chabi et al. 2008; Gouspillou et al. 2014).
Fortunately, exercise can serve to reduce the accumulation
of mitochondrial ROS and attenuate apoptotic cell death
in muscle (Ljubicic et al. 2009; Di Meo et al. 2019). Indeed,
endurance training is capable of increasing the expression
levels of a majority of the downregulated proteins that are
involved in energy metabolism, and of restoring the ATP
synthesis capability of aged muscle (Lanza et al. 2008).
Indeed, lifelong training, or even the adoption of physical
activity behaviours later in life, are established therapies
to improve mitochondrial health in order to preserve

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811
vitality. Individuals that have maintained high physical
activity throughout life have preserved mitochondrial
content and function (Lanza et al. 2008; Joseph et al.
2012). In addition, those who take to exercise at advanced
age are also capable of restoring mitochondrial content
and function to more closely resemble that of their
younger counterparts, when training programmes are
matched for relative intensity (Short et al. 2003; Carter
et al. 2015). Thus, exercise remains a reliable and
non-pharmacological strategy for the maintenance of
metabolic health into the late stages of life.
Mitochondrial health and the brain
While this review has focused on mitochondrial health in
skeletal muscle, the benefits of exercise are widespread,
affecting other organ systems. The effects of exercise
on mitochondrial health in other tissues has been
sparsely studied, but the recognition that muscle secretes
myokines, or exerkines, during exercise, suggests that
the health benefits of exercise may include muscle
activity-mediated benefits to other tissues, such as the
brain. The brain consumes about 20% of the body’s total
oxygen consumption, and it is almost entirely dependent
on mitochondrial energy production, as neurons have
limited glycolytic activity. Much of this energy is utilized
by neurons to establish membrane potentials, synthesize,
secrete and recycle neurotransmitters, as well as maintain
cellular Ca2+ homeostasis for effective neuronal signal
transmission. Mitochondria are also major producers
of ROS in the brain, and ROS-induced toxicity is an
established cause of pathologies observed in neuro-
degenerative diseases such as Alzheimer’s disease (AD),
Parkinson’s disease (PD), and multiple sclerosis (MS)
(Park et al. 2018). Deficits in cellular bioenergetics,
along with an oxidized redox environment, are the
major contributors to an age-related decline in neuro-
nal health, as evidenced by the dysfunctional TCA
cycle, compromised electron transport and altered
mitochondrial morphology evident in post-mortem
tissues of AD patients (Radak et al. 2016).
Exercise has long been associated with the wellbeing
of neuronal health, and it is routinely prescribed as
a therapeutic and preventative strategy in dementia
patients. Exercise also alters brain structure in neuro-
degenerative disease patients, mediating increases in
angiogenesis, hippocampal neurogenesis, synaptic
plasticity, and decreases in age-related brain atrophy
(Bernardo et al. 2016). Coincident with this are
exercise-induced alterations in mitochondrial function
and biogenesis in neurons. Voluntary exercise induced
increased uncoupling protein (UCP) 2 mRNA expression
and mitochondrial oxygen consumption in mouse
hippocampus, along with a concomitant increase in
dendritic spines and mitochondrial number in wild-type,
812 J. M. Memme and others
but not in UCP2 knockout mice (Dietrich et al. 2008).
Likewise, exercise promotes improved mitochondrial
function through enhanced complex I activity in the
brains of aged mice (Gusdon et al. 2017). Chronic exercise
also increased the levels of various mitochondrial TCA
enzymes and ETC activity in neurons, as well as the
synthesis and secretion of various neurotrophins, such as
brain derived neurotrophic factor (BDNF) (Navarro et al.
2004; Ding et al. 2006; Marques-Aleixo et al. 2015). BDNF
signalling is linked to mitochondrial health because it
improves the respiratory coupling efficiency of synaptic
mitochondria, it upregulates antioxidant enzymes, and
it mediates PGC-1α-induced mitochondrial biogenesis
(Marosi & Mattson, 2014). Such adaptations induced by
chronic exercise can reduce harmful redox aberrations
observed in AD patients.
How might exercise modulate mitochondrial health in
the brain (or in other tissues)? When muscle contra-
cts it releases a combination of peptides, lipids, mRNA,
microRNAs and mtDNA, collectively termed myokines
(Safdar et al. 2016; Trovato et al. 2019). These are trans-
ported via exosomes, small extracellular vesicles that can
be secreted into the extracellular environment and can
be taken up by distant cells via endocytosis (Feng et al.
2010; Whitham et al. 2018). The finding that intra-
cellular Ca2+ can influence vesicular secretion garnered
interest in skeletal muscles, because Ca2+ release by SR
signals muscle contraction and leads to changes in gene
expression (Safdar et al. 2016). During contractile activity,
the secretome contains hundreds of myokines, which may
contribute to adaptations in various organs in a paracrine
or endocrine fashion (Giudice & Taylor, 2017; Hoffmann
& Weigert, 2017). Some of these include members of
the interleukin (IL) family of proteins, BDNF, fibroblast
growth factor 21 (FGF-21), irisin, and vascular endothelial
growth factor (VEGF), and these can potentially mediate
signalling between muscle and various organs, including
the brain, and other tissues, thereby transmitting the
beneficial effects of exercise to these tissues (Pedersen &
Febbraio, 2012; Covington et al. 2016; Lu et al. 2016; Safdar
et al. 2016; Gomes et al. 2017; Kim & Song, 2017). Physical
activity has long been established to have a beneficial role
in preventing neurodegenerative diseases and improving
the cognitive abilities of affected people (Vecchio et al.
2018). Investigating the role of exercise-induced myokines
in influencing mitochondrial health in other tissues, such
as the brain, is worthy of further study.
Conclusion and future perspectives
The role of mitochondria in contributing to overall health
and vitality is continually coming into sharper focus,
evidenced by the increasing volume of mitochondrial
research that is being conducted within the medical science
community. Indeed, these organelles are at the nexus of a
J Physiol 599.3
variety of signalling pathways and biological processes that
impact on cellular health, beyond ATP provision. Skeletal
muscle is of significant interest in that it comprises a large
proportion of body mass, it is highly metabolic, and its
mitochondrial content is malleable to external stimuli.
Thus, muscle represents an ideal tissue for the study of
mitochondria in health and disease.
Scientists are now beginning to appreciate the molecular
mechanisms by which mitochondrial content, function
and dynamics are maintained within the cell. Regulation
of the finely tuned balance between biogenesis and
mitophagy, the maintenance of a healthy network of
organelles, and their ability to interconnect where
appropriate in order to enhance the efficiency of the
functional reticulum, are areas of important future study.
In addition, a greater understanding of the redundancies
in the nuclear-derived signalling leading to mitochondrial
turnover, as well as the retrograde signalling from
the organelle to the nucleus, also warrant considerable
research effort. Elucidation of these signalling networks
can help identify pharmacological targets that would be
useful adjuncts to enhance mitochondria in the pre-
sence of an exercise stimulus. This would be of inter-
est to scientists and health care professionals, given the
decrements in mitochondria observed with age, as well
as the multitude of secondary diseases that may arise
which depend on mitochondrial function, such as type
2 diabetes and obesity. Thus, exercise remains our best
behavioural medicine for improving mitochondrial health
and individual longevity.
From an applied perspective, while endurance
exercise training has long been appreciated to enhance
skeletal muscle aerobic capacity through augmented
mitochondrial quality control, content and function,
alternative exercise training modalities are gaining traction
as viable interventions capable of inducing similar
improvements in mitochondria, while condensing a
similar workload into a shorter period, and thus achieving
a level of time efficiency per exercise bout. Further work
exploring different training programmes that improve the
efficiency of the stimulus and foster an increase in public
adoption present an attractive area of study as well.
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Additional information
Competing interests
The authors have no competing interests to declare.
Author contributions
All authors contributed to writing the manuscript. J.M.M.
and D.A.H. conceived of the review, identified and inter-
preted relevant studies for inclusion, and critically revised the
manuscript. All authors approved of the final manuscript and
agreed to be accountable for all aspects of the work. All persons
designated as authors qualify for authorship, and all those who
qualify for authorship are listed.
Funding
Our laboratory is funded by an operating grant from the Natural
Sciences and Engineering Research Council of Canada (NSERC;
grant number 38462) to D.A.H. and D.A.H. is a Tier 1 NSERC
Canada Research Chair in Cell Physiology. J.M.M. is funded by
a NSERC CGS-D.
Keywords
ageing, exercise training, lysosomal biogenesis, mitochondrial
biogenesis, mitochondrial quality control, mitophagy, skeletal
muscle, UPRmt