Reactome: A Curated Pathway Database

Mitochondrial biogenesis

Stable Identifier
R-HSA-1592230
Type
Pathway
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

Mitochondrial biogenesis and remodeling occur in response to exercise and redox state (reviewed in Scarpulla et al. 2012, Handy and Loscalzo 2012, Piantadosi and Suliman 2012, Scarpulla 2011, Wenz et al. 2011, Bo et al. 2010, Jornayvaz and Shulman 2010, Ljubicic et al. 2010, Hock and Kralli 2009, Canto and Auwerx 2009, Lin 2009, Scarpulla 2008, Ventura-Clapier et al. 2008). It is hypothesized that calcium influx and energy depletion are the signals that initiate changes in gene expression leading to new mitochondrial proteins. Energy depletion causes a reduction in ATP and an increase in AMP which activates AMPK. AMPK in turn phosphorylates the coactivator PGC-1alpha (PPARGC1A), one of the master regulators of mitochondrial biosynthesis. Likewise, p38 MAPK is activated by muscle contraction (possibly via calcium and CaMKII) and phosphorylates PGC-1alpha. CaMKIV responds to intracellular calcium by phosphorylating CREB, which activates expression of PGC-1alpha.
Deacetylation of PGC-1alpha by SIRT1 may also play a role in activation (Canto et al. 2009, Gurd et al. 2011), however Sirt11 deacetylation of Ppargc1a in mouse impacted genes related to glucose metabolism rather than mitochondrial biogenesis (Rodgers et al. 2005) and mice lacking SIRT1 in muscle had normal levels of mitochondrial biogenesis in response to exercise (Philp et al. 2011) so the role of deacetylation is not fully defined. PGC-1beta and PPRC appear to act similarly to PGC-1alpha but they have not been as well studied.
Phosphorylated PGC-1alpha does not bind DNA directly but instead interacts with other transcription factors, notably NRF1 and NRF2 (via HCF1). NRF1 and NRF2 together with PGC-1alpha activate the transcription of nuclear-encoded, mitochondrially targeted proteins such as TFB2M, TFB1M, and TFAM.

Literature References
PubMed ID Title Journal Year
19008463 Minireview: the PGC-1 coactivator networks: chromatin-remodeling and mitochondrial energy metabolism Mol. Endocrinol. 2009
18430751 Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha Cardiovasc. Res. 2008
20933024 Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network Biochim Biophys Acta 2011
20533901 Regulation of mitochondrial biogenesis Essays Biochem. 2010
21543634 Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle Am J Physiol Regul Integr Comp Physiol 2011
19076454 Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator Ann N Y Acad Sci 2008
19682549 Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging Biochim Biophys Acta 2010
22265687 Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes Biochim. Biophys. Acta 2012
19575678 Transcriptional control of mitochondrial biogenesis and function Annu Rev Physiol 2009
22146081 Redox regulation of mitochondrial function Antioxid. Redox Signal. 2012
21629705 Mitochondria and PGC-1? in Aging and Age-Associated Diseases J Aging Res 2011
19276888 PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure Curr Opin Lipidol 2009
22817841 Transcriptional integration of mitochondrial biogenesis Trends Endocrinol. Metab. 2012
20649548 Redefining the role of mitochondria in exercise: a dynamic remodeling Ann. N. Y. Acad. Sci. 2010
21757760 Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-{gamma} Coactivator-1{alpha} (PGC-1{alpha}) Deacetylation following Endurance Exercise J Biol Chem 2011
15744310 Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1 Nature 2005
19262508 AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity Nature 2009
Participants
Participant Of
Orthologous Events