Mitochondrial Biogenesis

Mitochondrial biogenesis is a self-renewal route in which new mitochondria are generated from those already existing, launched in response to the energy demand triggered by developmental signals and environmental stressors. ^[1] It maintains the homeostasis of mitochondrial mass and function and is one of the opposing mechanisms, together with mitophagy, that tightly regulate mitochondrial mass and quality. ^{[1] [2]}

The transcriptional coactivator PGC-1alpha is a master regulator of mitochondrial biogenesis and a central player in the transcriptional control of mitochondrial components. ^{[3] [4]} PGC-1alpha induces mitochondrial biogenesis by activating transcription factors including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A that drives transcription and replication of mitochondrial DNA. ^[5] The entire protein-coding capacity of mitochondrial DNA is devoted to the synthesis of 13 essential subunits of the inner-membrane respiratory complexes, while the majority of respiratory proteins are derived from nuclear genes. ^[6] PGC-1alpha itself is regulated by the energy sensors AMP-activated protein kinase and SIRT1, which modify its activity through phosphorylation and deacetylation respectively. ^{[5] [7]}

AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. ^[5] PGC-1alpha-mediated regulation of mitochondrial quality may affect age-related mitochondrial dysfunction and insulin sensitivity. ^[3] During aging and disuse, dysregulation of the mitochondrial network and reductions in muscle mass are associated with impaired mitochondrial biogenesis and function. ^[8]

Exercise activates signaling that provokes increases in mitochondrial biogenesis, and remains the most potent behavioural approach for improving mitochondrial health. ^{[8] [9]} Administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of acute kidney injury and diabetes mellitus. ^[10] Understanding the molecular mechanisms regulating mitochondrial biogenesis may provide potentially important novel therapeutic targets given the role of mitochondrial dysfunction in numerous diseases and in aging. ^[5]