Figure 1.

Regulation of mitochondrial biogenesis at the transcriptional and translational level. At the transcriptional level, the PGC-1α-NRF-1/2-TFAM pathway is the master regulator of mitochondrial biogenesis. Increased AMP/ATP ratio, NAD⁺/NADH ratio and Ca²⁺ levels, which are part of mitochondrial feedback mechanisms within the cell, result in activation of AMPK, PKA, SIRT1 and CaMK that in turn lead to PGC-1α stimulation. Once activated, PGC-1α promotes transcription of nuclear-encoded mitochondrial genes via NRF-1/2 and transcription of mitochondrial-encoded genes via expression of TFAM. At the translational level, the insulin-induced PI3K/AKT/mTORC1 pathway plays a major role in mitochondrial biogenesis. Via activation of eIF4E, mTORC1 increases the translation of nuclear-encoded mitochondrial proteins, which are imported into mitochondria. AKT, however, also has an effect on transcription via inhibition of FOXO1 and consequent activation of PGC-1α. Furthermore, AMPK is also a substrate of AKT, which is inhibited by AKT-induced phosphorylation. Finally, AMPK and mTORC1 can inhibit each other by direct phosphorylation.