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Role of p53 Within the Regulatory Network Controlling Muscle Mitochondrial Biogenesis

Saleem, Ayesha1,2; Carter, Heather N.1,2; Iqbal, Sobia1,2; Hood, David A.1,2,3

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Exercise and Sport Sciences Reviews: October 2011 - Volume 39 - Issue 4 - p 199-205
doi: 10.1097/JES.0b013e31822d71be
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As the incidence and prevalence of cancer increases, the costs associated with the care, treatment, and management of cancer and associated comorbidities continue to surge. It is imperative that the molecular biology and pathology of cancer is studied to fine-tune potential therapeutic strategies available for tumor treatment. The powerful apoptogenic and growth-suppressive activity of the tumor suppressor protein p53, coupled with the fact that p53 is inactivated or mutated in 50% of all tumors, make it an attractive target for cancer therapeutics.

The activation of p53 is an established event orchestrated by the cell in response to a stress signal. Once activated, p53 mounts a reactive response to the imposed insult by inducing cell cycle arrest and facilitating DNA repair or, in the case of irreparable damage, by promoting cell death or apoptosis (17). Emerging evidence indicates that p53 also executes an adaptive response to metabolic stress by controlling oxidative metabolism (20). Because it commonly is accepted that metabolic perturbations are a hallmark of cancer progression, the p53-mediated regulation of energy metabolism is being studied as a possible therapeutic modality in cancer treatment and management.

Endurance exercise is one of the best possible means available to modulate whole body metabolism. In addition to improving metabolic performance, a plethora of short-term and longitudinal studies have shown that regular physical activity extends life expectancy and reduces morbidity. Elucidating the underlying causes and molecular signaling events, such as the role of p53 in the adaptive response to endurance exercise, carries great significance for the treatment of physical inactivity-related and impaired metabolism-related diseases such as obesity, insulin resistance, type 2 diabetes, cancer, and cardiovascular diseases that overburden our health care systems.

Here, we hypothesize that p53 and its activation (26) are involved in the complex network of transcriptional (12,13,31) and posttranscriptional events underlying exercise-mediated adaptations in mitochondrial synthesis (Fig. 1) that work in concert to orchestrate improvements in oxidative metabolism. We also summarize the known conduits by which p53 contributes to this process and allude to directions for future research that could further implicate p53 as a vital player in the regulatory network controlling muscle mitochondrial biogenesis.

Figure 1
Figure 1:
The nexus of mitochondrial biogenesis. A coordinated network of events transpires to orchestrate an increase in mitochondrial content and the maintenance of organelle quality. Signaling events, such as the activation of AMP kinase (AMPK), reactive oxygen species (ROS), and p38 mitogen-activated protein kinase (MAPK), trigger downstream regulatory transcription factors (p53, proliferator-activated receptor γ coactivator-1α (PGC-1α)) to bind to the promoter regions of other genes important for mitochondrial synthesis and function. These mitochondrial-related genes are transcribed, and their messenger RNA (mRNA) transcripts can be stabilized or destabilized based on the presence of mRNA regulatory factors. Many mitochondrial proteins are synthesized as precursor proteins with cleavable N-terminal presequences that are subsequently imported into the mitochondria by the protein import machinery. In addition tode novo mitochondrial protein synthesis, mitochondrial content and quality also are determined in part by the rates of mitochondrial autophagy (mitophagy), apoptosis, and organelle fission and fusion. All of these pathways conspire together to maintain a pool of functional and viable mitochondria within the muscle. Aberrations in any of these factors can impinge upon the integrity and amount of mitochondria within the muscle.


A highly malleable tissue, skeletal muscle exhibits a remarkable range of plasticity in response to a number of physiological and pathophysiological stimuli. With endurance exercise training, there is a change in substrate metabolism, an increase in mitochondrial content, and an improved exercise tolerance. Since this first was noted many years ago (11), many researchers have confirmed and extended these observations. The increase in mitochondrial content per gram of tissue with exercise is termed mitochondrial biogenesis. This is evident in both subsarcolemmal mitochondria, those located underneath the sarcolemma membrane, and in intermyofibrillar mitochondria, those interspersed between the myofibrils (19).

The process of mitochondrial biogenesis is complex, requiring the coordinated induction of more than 1500 proteins encoded by both the nuclear and mitochondrial genomes as recently reviewed (28). Control over this process is mediated by a number of transcriptional regulators, including the members of the peroxisomal proliferator-activated receptor γ coactivator-1 (PGC-1) family, nuclear respiratory factor 1/2 (NRF-1/2), cAMP response element binding protein, initiator element binding factor (YY1), estrogen-related receptor α/γ, thyroid hormone receptor family, and myocyte-enhancing factor 2, among several others. Of the numerous studies devoted to defining the transcriptional regulation of mitochondrial biogenesis, an exciting and emerging role for p53 has surfaced (see below). However, of this myriad of factors, the lion‘s share of the attention has been given to the transcriptional coactivator, PGC-1α.

Role of PGC-1α in Mitochondrial Biogenesis

The PGC-1 family consists of PGC-1α-, PGC-1β-, and PGC-1-related coactivator. PGC-1α is a transcriptional coactivator and a critical regulator of the transcription of nuclear genes encoding mitochondrial proteins. It has been implicated as a key mediator of the adaptive response to exercise in skeletal muscle (30).

Many of the putative signals triggering exercise-induced adaptations in skeletal muscle are activators of PGC-1α. For example, p38 mitogen-activated protein kinase (MAPK) can phosphorylate PGC-1α at three sites, releasing PGC-1α from a repressor protein (30). The AMP kinase (AMPK) activates PGC-1α by phosphorylating threonine-177 and serine-538 residues, leading to mitochondrial biogenesis (30). We have shown that AMPK activation by AICAR (Calbiochem, La Jolla, CA), a well-known pharmacological drug that specifically triggers AMPK and elicits an increase in PGC-1α promoter activity, as well as messenger RNA (mRNA) expression (13). The PGC-1α function is inhibited by acetylation and the NAD+-dependent type III deacetylase, SIRT1, deacetylates, and activates PGC-1α (30). Cellular reactive oxygen species also have been identified as a stimulus-regulating PGC-1α in promoting mitochondrial biogenesis and respiration (30). We recently have demonstrated that reactive oxygen species augment PGC-1α promoter activity and mRNA expression in murine myotubes, an effect that was abolished when the antioxidant, N-acetylcysteine was present (12). Furthermore, current work has shown that AMPK must phosphorylate PGC-1α before SIRT1 deacetylation for the full activation of PGC-1α and its downstream target genes, indicating that the different signaling pathways work in concert to activate PGC-1α (30).

The posttranslational modifications of PGC-1α lead to its activation and its redistribution within the cell. In the nucleus, PGC-1α coactivates transcription factors regulating mitochondrial biogenesis, including NRF-1/2, estrogen-related receptor α, peroxisomal proliferator-activated receptors, and myocyte-enhancing factor 2 (30). These transcription factors regulate the promoters of genes involved in electron transport chain (ETC) function and fatty acid oxidation. Endurance exercise facilitates this coactivator function by causing a shift in the subcellular localization of PGC-1α from the cytoplasm to the nucleus. This occurs before any exercise-induced increase in PGC-1α protein expression (33). Moreover, it has recently been reported that endurance exercise mediates the translocation of PGC-1α to the mitochondria where it may serve as a coactivator for mitochondrial transcription factor A (Tfam) on mitochondrial DNA (mtDNA) (24). PGC-1α also increases the expression of Tfam through the coactivation of NRF-1/2. Tfam is required for mediating the transcription of 13 ETC subunits, 2 rRNAs, and 22 tRNAs encoded by the mtDNA and also controls mtDNA copy number and maintenance (8). In this manner, PGC-1α contributes to the coordinated regulation of the nuclear and mitochondrial genomes during mitochondrial biogenesis.

Studies conducted using PGC-1α transgenic and knockout (KO) mice also support an important role for PGC-1α in the regulation of mitochondrial function and exercise adaptations. Muscle-specific PGC-1α overexpression results in similar adaptations as those seen with endurance exercise training, including higher mitochondrial content, enhanced fat oxidation and lower glycogen utilization during exercise, and an increased endurance capacity (30). We have illustrated that mice deficient in PGC-1α have reduced basal mitochondrial content and impaired respiratory function (2), yet the endurance exercise-induced adaptive gene response is not abolished in these mice (16). Using a cell culture model of chronic contractile activity, we confirmed that PGC-1α was necessary for most, but not all, of the exercise-mediated changes culminating in mitochondrial biogenesis (31). Together, these data imply redundancy in the molecular mechanisms regulating metabolic homeostasis, such that other members of the PGC-1 family or novel transcription factors, such as p53, play a vital part in exercise-induced mitochondrial synthesis.


The tumor suppressor protein p53 is a master stress response factor well known for its pleiotropic effects on cell cycle arrest, apoptosis, prooxidant and antioxidant activity, angiogenesis, DNA repair, differentiation, fertilization, aging, and senescence (17). In addition to serving as the "Guardian of the Genome" (15) under stressful conditions, mounting evidence indicates that p53 plays a vital role in the maintenance of energy homeostasis in nonstressful environments. Notably, p53 has been demonstrated to be involved in the maintenance of mitochondrial biogenesis (20). Lack of p53 impairs aerobic capacity and exercise performance and results in greater fatigue in p53 KO mice highlighting a role for p53 in skeletal muscle health (26). Although the complex mechanisms underlying this effect have not been fully elucidated, tangible progress has been made in illustrating how p53 contributes substantially to the maintenance of mitochondrial content and function.

Activation of p53

p53 can be activated by mild, as well as by more severe, genotoxic stress signals, leading to the understanding that p53 plays an important role during normal health and development. Studies of cells in culture subject to nutrient (i.e., glucose) deprivation demonstrated an increase in the activation of AMPK, leading to the downstream phosphorylation of p53 at serine 15 (p53Ser15). This is a posttranslational modification associated with an increased stability and activity of p53 (6). Moreover, p53Ser15 is a bona fide target of p38 MAPK under conditions of cellular stress (17). Interestingly, we previously have shown that an acute bout of contractile activity results in concomitant increases in AMPK, p38 MAPK, and p53Ser15 phosphorylation (26). This suggests the possibility that p53 may be involved in endurance exercise-induced mitochondrial biogenesis upon posttranslational modifications induced by AMPK and/or p38 MAPK signaling cascades.

p53 and Mitochondrial Function

A commonly used indicator of mitochondrial content is cytochrome c oxidase (COX) activity. The COX complex, made up of 13 subunits that are both nuclear- and mtDNA-encoded plays a crucial role in aerobic respiration by catalyzing the transfer of electrons from reduced cytochrome c to molecular oxygen. Ablation of a functional p53 protein manifests as reduced COX activity (22,26). This decrease in COX enzyme activity has been attributed to the transcriptional and posttranscriptional control exerted by p53 on the expression of COX subunit I and COX subunit II (35), respectively. In addition, p53 transcriptionally regulates the synthesis of COX 2 (SCO2), a protein required for the assembly of mtDNA-encoded COX II subunit into the COX complex (22). SCO2 defects have been linked causally to aerobic respiratory failure and terminal cardioencephalomyopathy (22). The lower rate of mitochondrial respiration observed in p53 KO cell lines was rescued by the transient transfection of SCO2 (22), indicating that this is an important pathway through which p53 promotes optimal mitochondrial biogenesis.

A number of studies also have provided direct evidence for the presence of p53 response elements in the promoter regions of nuclear-encoded mitochondrial proteins related to metabolism, such as apoptosis inducing factor (AIF), heat shock protein 70 (hsp70) and hsp90, and Tfam. Although AIF is known for its role in the induction of apoptosis, during basal conditions, AIF contributes to efficient oxidative phosphorylation by promoting the proper assembly and function of mitochondrial respiratory complex I. Hsp70 and hsp90 are cytosolic chaperones that assist in the targeting of mitochondrial-destined proteins to the mitochondria. As well, Park and colleagues (23) demonstrated that the presence of p53 is a determinant of both Tfam expression and mtDNA content. This suggests that p53 uses the regulation of Tfam as a conduit through which it can control the process of mitochondrial biogenesis.

p53 and Mitochondrial DNA

The small number of proteins encoded by the mtDNA is vital for ETC function. Mutations in mtDNA have a range of pathological consequences, with approximately 250 known disease-causing mutations now reported. Furthermore, mutations in the nuclear DNA-transcribed proteins affecting mtDNA mutations are even more frequent, thus increasing the genetic load of mtDNA dysfunction. p53 can be imported into mitochondria, and several studies have concluded that it may be involved in modulating mtDNA-encoded gene expression and stability (1,14,23,34). The presence of a putative p53 response element in mtDNA indicates the possibility that p53 could be involved directly in the transcription of mtDNA (10). Indeed, p53 KO mouse embryos displayed a deficiency in mtDNA-encoded 16S rRNA transcripts (5). p53 also promotes and maintains mitochondrial genomic stability directly 1) via its inherent 3‘ → 5‘ exonuclease activity (3); 2) by physically interacting with Tfam and regulating the binding of Tfam to damaged mtDNA (34); and 3) by enhancing the function of mtDNA polymerase gamma (pol γ), the only DNA polymerase in the mitochondria that is responsible for mtDNA replication and repair (1). Clearly, p53 has a validated and significant impact on maintaining mtDNA transcription and integrity.

p53 and Glycolysis

Endurance exercise training is known to favor an increased reliance on aerobic metabolism, rather than glycolysis, as means of energy production in muscle. Coincidentally, along with its effect on promoting optimal mitochondrial function and mtDNA integrity, p53 appears to suppress glycolysis as well. A novel p53-transactivated gene called TP53-induced glycolysis and apoptosis regulator lowers fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis (4). Additionally, p53 can induce the degradation of phosphoglycerate mutase, leading to decreased glycolytic flux (20). Because one of the hallmarks of cancer is a shift from aerobic to glycolytic metabolism, a process known as the Warburg effect (20), the p53-mediated suppression of glycolysis is in line with its role in cancer suppression. It remains to be seen whether the exercise-induced suppression of glycolysis, and enhanced reliance on mitochondrial metabolism, is in part relayed by the recruitment and activation of p53.


Autophagy is the process of controlled degradation and recycling of intracellular material to replenish nutrient stores and thus ensure cell survival. Autophagy removes protein aggregates and dysfunctional organelles, such as mitochondria, that may compromise the integrity of the cell. Decreased rates of autophagy are implicated in various neurological and metabolic diseases. On the other hand, endurance exercise has been shown to activate autophagy (27), and this may serve to rid the cell of dysfunctional mitochondria (mitophagy) (9).

p53 is either a positive or a negative regulator of autophagy, depending on the cellular localization of the protein and cellular stress conditions (21). During cellular stress when p53 is localized in the nucleus, it promotes the expression of target genes that induce autophagy. Some of the genes identified include AMPK subunits β1 and β2, tuberous sclerosis complex 2 (TSC2), Sestrin2, damage-related autophagy modulator, and death-associated protein kinase 1 (21). In particular, AMPK, TSC2, and Sestrin2 are able to exert a negative influence over the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway that participates in cell growth and metabolism and negatively regulates autophagy (7,21). Therefore, nuclear-localized p53 can increase autophagic flux by suppressing mTORC1, a classic inhibitor of autophagy.

Conversely, during basal, non-stressful conditions, a large fraction of p53 resides in the cytoplasm. This cytoplasmic pool of p53 appears to inhibit autophagy (29). For example, an elevated basal content of autophagosomes is evident in p53 KO mice, suggesting that autophagy is stimulated in the absence of p53, and there is no further increase in these autophagy vesicles upon starvation, as is commonly manifest in wild-type (WT) mice (29). Thus, the absence of cytoplasmic p53 may allow autophagy to proceed at a maximal rate. It therefore appears that p53 may serve as a rheostat of autophagic signaling, involved in adjusting the rate of autophagy depending on its localization and the presence or absence of cell stress. Further research on the coordinated interplay between p53 and mTORC1 on the rate of autophagy, and the subsequent affect on mitochondrial turnover, is warranted.


Mitochondria are dynamic organelles, capable of adapting to energy perturbations within the cell. The maintenance of mitochondrial morphology depends on equilibrium between the states of fission and fusion. Fusion involves the merging of the inner and outer membranes, as well as the mixing of mitochondrial material. On the other hand, fission divides the mitochondrial network into smaller organelles. Disruptions in either of these opposing processes can lead to developmental defects and disease, suggesting that proper maintenance of mitochondrial morphology is critical for normal cell function.

p53 has been linked to the regulation of both mitochondrial fission and fusion proteins. Knockdown of p53 has been reported to reduce mitochondrial fission, likely because of the ability of p53 to transcriptionally upregulate the expression of the fission protein Drp1 (18). On the other hand, a consensus p53 binding site has been identified within the promoter region of Mfn2, an important fusion protein. p53 has been illustrated to positively modulate the promoter activity and protein expression of Mfn2 (32). To date, there is no evidence that a net increase or decrease in mitochondrial network formation occurs in the absence of p53. However, we have noted previously that lack of p53 results in altered cristae formation in subsarcolemmal mitochondria and reduced reticular network in the intermyofibrillar mitochondria isolated from p53 KO mice (26). This alludes to the involvement of p53 in determining muscle mitochondrial morphology, and further study is required to fully understand the role of p53 in mitochondrial structural dynamics.


The disruption of p53 expression carries significant physiological repercussions, as evident by the greater fatigability and reduced exercise capacity observed in p53 KO animals (22,23,26). To implicate p53 in endurance exercise-induced mitochondrial adaptations, it is likely that p53 should be modified posttranslationally by contractile activity and/or that its subcellular localization be modified as a result of an exercise stimulus. We have shown that contractile activity exercise induces an increase in p53Ser15 phosphorylation (26), classically linked to the increased stability and activity of the protein. This enhanced phosphorylation could be due to a combined effect of the activation of p38MAPK and AMPK, both of which are canonical exercise-activated kinases. This may confer a change in p53 cellular localization to enter the nucleus or the mitochondrion, although this remains to be demonstrated. These changes in localization could have a profound impact on the expression of nuclear and mitochondrial genes.

p53 does appear to have an influence on the expression of PGC-1α, a coactivator that is important for normal mitochondrial adaptations to contractile activity. Our earlier work identified a putative p53 response element in the promoter region of PGC-1α identified through in silico analysis (13). PGC-1α protein expression also was reduced in muscle of p53 KO animals (26). Thus, this suggests that p53 is a positive regulator of PGC-1α gene expression. In distinct contrast, a recent study has reported that telomere dysfunction elicits increased expression and activation of p53, which then consequently binds to both PGC-1α and PGC-1β promoters, and represses their expression in mouse embryonic fibroblasts (25). Deleting germline p53 in these telomerase-deficient mice restored PGC-1α/β expression and rescued the mitochondrial oxidative pathology present in these mice (25). These results are in complete opposition to those that indicate the importance of p53 for the maintenance of mitochondrial integrity. It may be that the effect of p53 on PGC-1α/β expression observed in this study is tissue specific or that the signaling milieu in cells from the telomere dysfunctional animals varies significantly from a normal mouse. It is clear from studies using KO animals that the loss of p53 does not result in higher PGC-1α/β expression, nor does it improve mitochondrial function. Thus, further work clearly is required to fully expound the relation between p53 and PGC-1α and the resultant effects on mitochondrial biogenesis.

Integrative Role of p53 in Exercise-Induced Mitochondrial Biogenesis - Future Directions

Despite a growing appreciation for a widening role for p53 in mitochondrial biogenesis and function, there is very limited literature available, which has analyzed the necessity of p53 for endurance exercise-induced mitochondrial biogenesis in muscle, as most of the research on p53 has been conducted in cancer cell lines. We have shown that in response to 8 wk of wheel running, p53 KO mice have a similar relative increase in COX activity (∼26%) as WT mice, despite running fivefold lower distances, suggesting that p53 may be important, but not required, for exercise-mediated increases in muscle oxidative capacity (26). Park et al. (23) reported that 5 wk of treadmill training improved peak oxygen consumption, work capacity, and blood lactate levels in WT mice but not in p53 KO mice, underscoring the value of p53 for the accrued benefits of endurance exercise.

As illustrated in Figure 2, p53 affects mitochondrial biogenesis by exerting control over a plethora of different cellular pathways. p53 can transcriptionally activate important factors such as PGC-1, Tfam, AIF, and SCO2 that lead to mitochondrial biogenesis. p53 also can translocate to the mitochondrion and interact with mtDNA, Tfam, and pol γ, contributing to mtDNA-mediated transcription and ensuring the integrity of the genome. Clearly, the cellular localization of p53 is important in determining the consequences of its actions. Thus, it would be particularly interesting to deduce whether exercise induces a posttranscriptional modification in p53, culminating in its cellular relocalization. The presence of p53 in the nucleus or extranuclear regions also dictates its effect on autophagy. The autophagic destruction of dysfunctional or fragmented mitochondria is an important pathway for the maintenance of a constant mitochondrial content. We hypothesize that p53 may play an important role in the removal of damaged mitochondria with endurance exercise. Furthermore, it may be that an exercise-induced activation of p53 could lead to the transcription of both Mfn2 and Drp1, thus maintaining optimal rates of fission and fusion in the cell, which are required to maintain a healthy mitochondrial pool. Further research in these areas is required to prove/disprove these hypotheses.

Figure 2
Figure 2:
Regulation of mitochondrial biogenesis by p53. As a conventional nuclear transcription factor, p53 can induce the transcription of proteins involved in mitochondrial turnover (autophagy, fission, and fusion) and mitochondrial synthesis. p53 transcribes proautophagic proteins such as AMP-activated protein kinase (AMPK) subunits β1 and β2, tuberous sclerosis complex 2 (TSC2), and others (see the text) to induce autophagy. It also evokes the transcription of mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1) that contribute to mitochondrial fusion and fission, respectively. Autophagy of dysfunctional mitochondria and mitochondrial fission/fusion flux may work in concert to ensure efficient mitochondrial turnover and maintenance of healthy mitochondria. Furthermore, p53 also transcribes genes involved in controlling mitochondrial synthesis such as mitochondrial transcription factor A (Tfam), synthesis of cytochromec oxidase 2 (SCO2), and apoptosis inducing factor (AIF), among others. These proteins subsequently are imported into the mitochondria where they perform specific functions. Tfam is responsible for mtDNA replication and transcription. SCO2 is necessary for the proper assembly of subunit II in complex IV in the electron transport chain (ETC), and AIF contributes to the optimal assembly and function of complex I within the ETC. Lastly, p53 translocates into the mitochondria and positively affects mtDNA transcription and genome integrity by interacting with Tfam and the mtDNA repair enzyme polymerase γ (POLγ). p53 also has inherent DNA repair activity. Whether exercise causes posttranslational modification(s), or changes in the subcellular localization of p53 (?) to trigger the nuclear- and/or mitochondrial-specific effects, has yet to be elucidated.


Regularly performed endurance exercise exerts a plethora of adaptive effects leading to a multitude of health benefits, such as reduced risk of cardiovascular disease, obesity, type 2 diabetes, and cancer. These are mediated by the activation of various transcription factors and cellular signaling pathways. p53 has emerged as a relatively new player in this field, as it is now established to have an important impact on mitochondrial function and content. Several epidemiological studies have indicated firmly that regular endurance exercise results in a reduced risk of cancer. Whether endurance exercise potentiates the systemic activation of the tumor suppressor protein p53 in multiple tissues and thereby retards cancer incidence/growth is not known. However, it is intriguing to speculate that exercise-activated p53-dependent regulation of mitochondrial function and content could rescue the loss of oxidative capacity in muscle-wasting conditions such as cancer cachexia. Clearly, the integration of p53 within the regulatory network that contributes to endurance exercise-mediated metabolic and therapeutic adaptations in muscle is an exciting new avenue for study. Research in this area will contribute significantly to existing knowledge on exercise-induced mitochondrial biogenesis and provide impetus for further investigation into the metabolic aberrations that underlie cancer progression, with the hope of deciphering innovative therapies.


This work was supported by a Natural Science and Engineering Research Council of Canada (NSERC) grant and a Canadian Institute of Health Research (CIHR) grant to D. A. Hood. A. Saleem is a recipient of an NSERC Canada Graduate Scholarship. S. Iqbal is a recipient of an NSERC Postgraduate Scholarship. D. A. Hood holds a Canada Research Chair in Cell Physiology.


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exercise; gene expression; PGC-1α; mTOR; autophagy; fission/fusion

©2011 The American College of Sports Medicine