Controlling muscle mitochondrial content
Department of Biology, Queen's University, Kingston, Ontario, Canada, K7L 3N6
(e-mail: moyesc{at}biology.queensu.ca)
Accepted 28 August 2003
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Summary |
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Key words: skeletal muscle, oxidative phosphorylation, energy metabolism, peroxisome proliferator-activated receptor (PPAR), PPAR gamma coactivator 1 (PGC-1)
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Introduction |
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The process of building, maintaining and modifying muscle mitochondria is
very complex. Global changes in mitochondrial content require exquisite
coordination of hundreds of different genes located in the nucleus, in
parallel with the genes encoded by mitochondrial DNA (mtDNA). Synthesis of the
appropriate amounts of mitochondrial proteins also requires coordination of
protein synthesis in both the cytoplasm and mitochondria. Furthermore, most
enzymes within mitochondria change, more or less, in parallel to maintain
enzyme ratios or stoichiometries. For example, mitochondrial content differs
almost tenfold between red and white muscles of fish, yet the ratios of
mitochondrial enzymes are nearly identical
(Leary et al., 2003). How are
complex pathways altered, while retaining intrinsic stoichiometries in enzyme
levels?
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PGC-1 as a master regulator of mitochondrial gene expression |
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PGC-1 stimulates transcription by acting as a transcriptional
coactivator. It does not bind DNA directly, but attaches to transcription
factors already bound to DNA at specific recognition sequences, or elements
(Fig. 2). PGC-1
binds
heterodimers of transcription factors from the nuclear hormone receptor (NHR)
family, including the retinoic acid receptor (RxR), the thyroid receptor (TR),
and peroxisomeproliferator activated receptor (PPAR) (see reviews by
Knutti and Kralli, 2001
;
Puigserver and Spiegelman,
2003
). PGC-1
possesses an N-terminal leucine-rich region
that binds to the NHR. Both RxR and TR must bind their ligands (retinoic acid
and thyroid hormone, respectively) before they can bind PGC-1
. However,
PGC-1
can bind PPAR
even if no ligand is present. PGC-1
binds the heterodimer then undergoes a conformational change that allows it to
act as a docking site for other proteins. These proteins (e.g. SRC-1,
CBP/p300) remodel chromatin and help assemble the general transcriptional
machinery (Puigserver et al.,
1999
). Although first identified as a coactivator of PPAR
responsive genes, PGC-1
has since been shown to interact with other
transcription factors, such as myocyte enhancer factor 2c (MEF2c) (Micheal et
al., 2001) and NRF-1 (Wu et al.,
1999
). These interactions involve regions of PGC-1
that are
distinct from the domains involved in binding NHR. In addition to its role as
a transcriptional coactivator, PGC-1
also has a post-transcriptional
role, participating in mRNA processing and export (see
Knutti and Kralli, 2001
).
These transcriptional and post-transcriptional responsibilities place
PGC-1
at the center of regulatory pathways controlling genes for
proteins of aerobic metabolism.
|
Each element of the PGC-1 axis (ligands, NHRs, PGC-1
) can,
under the right conditions, stimulate many aspects of mitochondrial
biogenesis. PGC-1
levels correlate with muscle mitochondrial content in
both fiber type comparisons (Lin et al.,
2002a
) and adaptive responses to exercise training
(Pilegaard et al., 2003
).
Increasing PGC-1
levels directly, using transgenic mice or transfected
cells, increases mitochondrial content
(Lehman et al., 2000
;
Wu et al., 1999
). The levels
of the NHR and its ligands can also influence mitochondrial gene expression.
During fasting, increases in both PPAR
, and its putative ligand (fatty
acids) trigger an increase in enzymes of mitochondrial ß-oxidation
(Leone et al., 1999
;
Kersten et al., 1999
). This
could also be the mechanism by which high fat diets stimulate muscle
mitochondrial biogenesis, although the physiological ligands for PPARs remain
uncertain (Michalik et al.,
2003
; Puigserver and
Spiegelman, 2003
). Since the ability to stimulate transcription by
these NHR requires heterodimerization and DNA-binding, it can be regulated by
competition for binding partners and DNA elements. Interestingly, each of
these ligand-receptor combinations (PPAR agonists/PPAR, retinoic acid/RxR,
thyroid hormone/TR) can induce transcriptional changes in mitochondrial
proteins (e.g. Barbe et al.,
2001
). However, the interactions between these receptors are very
complex. For example, PPAR selectively inhibits the effects of TR by competing
for RxR (Juge-Aubry et al.,
1995
) and TR can, in turn, inhibit PPAR effects on transcriptional
activation (Miyamoto et al.,
1997
). The complexity of this PGC-1
axis allows animals to
create distinct tissue-specific metabolic properties and mount responses to
metabolic challenges. It also presents a challenge to comparative biologists
exploring the genetic basis of inter-species variation in aerobic
metabolism.
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How might evolutionary variation in the PGC-1 axis account for differences in mitochondrial content between animals? |
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PGC-1 variation
PGC-1 has multiple distinct binding sites for unrelated
transcriptional regulators. The N-terminal leucine-rich NHR-binding motif of
PGC-1
resembles that of other proteins which bind NHR
(Glass and Rosenfeld, 2000
).
It possesses unique structural features that bind other transcription factors,
such as NRF-1 and MEF2c. Its C-terminal RNA-binding motif resembles other
proteins that process mRNA. The structural motifs within PGC-1
suggest
an intriguing evolutionary history that probably involved fusion of functional
domains of different genes. In fact, very little is known of the evolutionary
history of PGC-1
. Since it was first reported
(Puigserver et al., 1998
), two
other coactivators have been identified that share structural features with
PGC-1
: PGC-1 related coactivator (PRC)
(Andersson and Scarpulla, 2001
)
and PGC-1ß (Lin et al.,
2002b
). Only PGC-1
has been studied in detail, but the
other members of the family appear to have similar capacities, although
distinct developmental profiles and inter-tissue distributions (see
Knutti and Kralli, 2001
). For
example, both PGC-1
and PGC-1ß induce mitochondrial proliferation
but there are subtle differences in the kinetics of proton leak
(St Pierre et al., 2003
). The
evolutionary origins of the gene family are also not yet established.
Zebrafish and Xenopus have expressed sequence tags (ESTs) or genes
that show superficial similarities to PGC-1
in either the N-terminal or
C-terminal regions (see Puigserver and
Speigelman, 2003
). Complete phylogenetic analyses have not yet
been reported but it will be interesting to see the relationship between the
origins of the ancestral PGC-1 gene, the evolutionary diversification the
PGC-1 gene family, and the diversification of muscle fiber types in tetrapod
evolution.
Transcription factor levels and properties
Evolutionary variation in transcription factor structure is a bit of a
paradox. Since each individual transcription factor may regulate hundreds of
genes, even subtle variations could have broad ramifications for gene
expression. For this reason, it has been argued that mutations in
transcription factors would have generally deleterious effects on integration
of gene expression, and would not be advantageous in the context of natural
selection (see Hsia and McGinnis,
2003). The very existence of transcription factor subfamilies,
however, argues that such subtle structural variations can be fixed within
populations, although gene duplications may be a necessary precondition.
Rather than disrupting genetic and metabolic integration, the subtly different
transcription factors within a family can provide the organisms with a degree
of developmental and physiological flexibility.
The diverse members of the NHR family probably arose from a single gene
early in metazoan evolution. Each lineage evolved distinct transcription
factors, although each NHR retains sufficient structural homology to be
recognized as a member of the family that arose more than 400 million years
ago. For example, the vertebrate RxR most closely resembles the invertebrate
Ultraspiracle gene product, which binds juvenile hormone III
(Jones and Sharp, 1997). Both
share a role in developmental regulation, but respond to completely different
regulatory ligands. While there is clearly great structural similarity in
these transcription factors, they mediate very different processes at the
cellular level. Even the multiple members of individual receptors, such as RxR
and PPAR subfamilies, possess distinct cellular roles despite very high
degrees of homology. Consequently, it is not beyond the realm of possibility
to imagine that a transcription factor variant might contribute to
interspecies differences in mitochondrial content in specific tissues, such as
skeletal muscle. On a micro-evolutionary scale, population-level polymorphisms
provide clear examples of how even single amino acid variations can alter
transcription factor function. For example, PPAR
exists as two allelic
variants that differ in position 12. People with the Ala12 allele
have a lower body mass index and lower risk of type 2 diabetes. When
recombinant constructs of the two PPAR alleles were compared, the
ALA12 variant had lower DNA binding activity
(Beamer et al., 1998
). Another
PPAR polymorphism (PRO115GLN) is adjacent to a regulatory serine
residue (SER114) (Hu et al.,
1996
), and correlates with obesity
(Ristow et al., 1998
).
Finally, an increase in a severe type of type 2 diabetes was associated with
two other polymorphisms (PRO467LEU, VAL290MET). The
effects of these polymorphisms were dominant, exerting negative effects on
people who where heterozygous. Collectively, the studies on allelic variation
demonstrate how subtle changes in structure could alter metabolic properties,
manifesting a phenotype that could be subject to natural selection.
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Mitochondrial content can also be controlled by post-transcriptional processes |
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Translational effectors
One mechanism to increase mitochondrial enzyme synthesis is to target the
translational processes. Translational control is important in many different
cell types, influencing both global translation and mRNA-specific translation
(Gray and Wickens, 1998;
Wilkie et al., 2003
). Many
nutrients exert their effects on protein synthesis through the mTOR (mammalian
target of rapamycin) signalling pathway that targets the translational
machinery, including initiation factors, elongation factors, their respective
binding proteins and the small ribosomal subunit (S6) (see
Proud, 2002
). For example,
iron-dependent gene expression exerts both specific and global controls on
expression in many tissues, particularly hemopoietic tissues such as
erythroblasts (Torti and Torti,
2002
; Templeton and Liu,
2003
). Iron-dependent repression of translation is probably
responsible for the coordinated reduction in mitochondria during erythrocyte
aging (Moyes et al., 2002
).
Mechanisms acting through global translational control have the potential to
alter the levels of proteins, without any change in transcriptional regulation
or the inherent stoichiometric relationships. For many individual mRNA
species, information in the 3' and 5' untranslated regions
controls the efficiency of translation (see
MacDonald, 2001
;
Wilkie et al., 2003
). The best
example of this type of regulation is cytoplasmic polyadenylation. A longer
poly(A)+ tail is better able to recruit the poly(A)+
binding protein, which is necessary to initiate translation.
While translational control has been shown to be important in many
contexts, its potential to explain inter-species differences in mitochondrial
content remains largely unexplored. The inherent differences in cytochrome
oxidase activities in Antarctic and polar eelpout, for example, appear to be
due to differences in translation, rather than transcription
(Hardewig et al., 1999).
Organelle stabilization
Mitochondria and mitochondrial macromolecules possess discrete half-lives
within cells. Proteins, lipid and DNA are readily damaged by oxidative stress
in particular. Superoxide production at electron transport system (ETS)
Complexes I and III can initiate a cascade of cytotoxic reactive oxygen
species (ROS) production, enhanced by metals that accelerate Haber-Weiss
reactions. Mitochondria can mitigate oxidative damage using anti-oxidant
defence pathways including ROS scavengers (e.g. thioredoxin, cytochrome
c) and anti-oxidant enzymes (e.g. glutathione peroxidase,
glutathione-S-transferase, Mn2+ superoxide dismutase). Some damaged
macromolecules can be repaired directly within mitochondria. For example,
mitochondria possess molecular chaperones, such as Hsp60 and Grp75, that
catalyze the folding of mitochondrial proteins. Cells can mount a
mitochondria-specific heat shock response
(Zhao et al., 2002) and cells
with enhanced mtHsp60 levels are more tolerant of oxidative damage
(Cabiscol et al., 2002
). Once
proteins become irreversibly damaged, they are degraded by proteases located
in each mitochondrial compartment. The Krebs cycle enzyme aconitase, with its
four iron-sulfur centers, is one of the most sensitive enzymes in
mitochondria. The mitochondrial Lon protease is very effective at detecting
and degrading mildly damaged aconitase
(Bota and Davies, 2002
).
Despite the anti-oxidant protection, repair chaperones and macromolecular
degradation pathways, mitochondria inevitably accrue damage. Once individual
mitochondria or regions of mitochondria accumulate enough damage, they are
targeted for degradation. The mitochondria fragment, then depolarize to
trigger autophagy (Elmore et al.,
2001
). These multifaceted quality control pathways ensure optimal
mitochondrial function, but they can also be used during periods of active
remodeling of cellular energetics. Acute reductions in energy demand can cause
relatively rapid reductions in mitochondrial content. For example,
anti-hypertensive treatment of spontaneously hypertensive rats can lead to a
30% reduction in mitochondrial content of the left ventricle within 10 days
(Leary et al., 2002
). In
principle, animals could increase the mitochondrial content of a tissue by
enhancing the half-life of mitochondrial macromolecules and the organelle
itself. Comparisons of muscles from different tissues
(Leary et al., 2003
) and
species (see Beckman and Ames,
1998
) show that anti-oxidant enzyme levels tend to covary with
mitochondrial capacity. However, the relative levels of the other aspects of
quality control pathways have not been explored.
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Models for studying evolutionary variation in energetics |
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With the growing awareness of the importance of considering phylogenetic
relationships, many researchers focus on intra-species variations that have
arisen since relatively recent geographic isolation events. Since mtDNA
sequence variation is often used to distinguish closely related populations
and species, it is possible to assess the impact of the variants on
mitochondrial function (reviewed in Moyes
and Hood, 2003). There are relatively few model systems where
clear differences in mitochondrial content arise among populations of a given
species, without the complications associated with physiological and
phenotypic plasticity. For example, wing polymorphic insects can display
profound population-level variation in flight muscle bioenergetics but these
differences in energetics are likely to be secondary to developmental
differences in life history strategies
(Winchell et al., 2000
).
Garland has used artificial selection to establish lines of mice that exhibit
profoundly different levels of voluntary exercise; active lines exhibit about
20% more mitochondrial enzymes than do sedentary lines, but both active and
sedentary lines elevate mitochondrial content to the same extent with exercise
training (Houle-Leroy et al.,
2000
). Thus, even population-level variation in the constitutive
expression of respiratory genes does not preclude the ability to induce
further increases with training. The genetic basis of population-level
variation in mitochondrial content in this powerful model remains unclear.
Much of the previous discussion has focused on the role of developmental
studies, inter-tissue comparisons, and pathophysiology in highlighting
potential steps at which natural selection could act. Advances in biomedical
sciences can have tremendous implications for comparative physiologists
studying essentially evolutionary variation. Because of the role of
mitochondria in numerous pathological conditions, our understanding of
mitochondrial genetics is greatly aided by studies involving targeted
mutations in transgenic mice. Transgenic mice can also be used to form
reasonable, testable hypotheses addressing the genetic basis of evolutionary
variants. Of the many lines of transgenic mice that exhibit elevated
mitochondrial enzyme levels, the effects of most transgenes can be attributed
to PGC-1 directly, or indirectly through its regulators such as CamK
(Wu et al., 2002
). Other
transgenic mice that exhibit increased mitochondrial enzymes are not so
clearly linked to PGC-1
. Myogenin overexpressing mice
(Hughes et al., 1999
) have
elevated slow muscle mitochondrial content. Knockout mice lacking
muscle-specific adenine nucleotide translocase demonstrate proliferation of
mitochondria (Graham et al.,
1997
). Mice overexpressing muscle-specific lipoprotein lipase also
show increased mitochondrial content, with enhanced capacity for fatty acid
oxidation (Hoefler et al.,
1997
). In many of these transgenic studies, it is important to
note that the mice often exhibited mild or severe myopathies and mitochondrial
abnormalities. This, of course, has important ramifications for studying the
genetic basis of evolutionary variation in mitochondrial biogenesis. Any
genetic change must lead to a coordinated increase in mitochondrial enzymes
that is functionally beneficial and limited to specific tissues. The answer
may lie in evolutionary variation in specific transcriptional regulators, but
it is important to keep in mind the potential role of other process, such as
post-transcriptional regulation.
Abbreviations used
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Acknowledgments |
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