Figure 1.

Schematic representation of the regulation of mitochondrial biogenesis. In response to external stimuli (e.g., skeletal muscle contraction or exercise), the nuclear genome coordinates the expression of nuclear and mitochondrial proteins. This pathway is triggered by the activation of signaling molecules, including AMP-activated protein kinase (AMPK), and converges on the expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), the master regulator of mitochondrial biogenesis. PGC-1α promotes its own expression as well as that of the nuclear respiratory factor 1 and 2 (NRF-1/2). NRF-1 and 2 bind and up-regulate the expression of nuclear genes encoding mitochondrial proteins as well as the expression of mitochondrial transcription factor A (TFAM), which is subsequently transported into mitochondria. Here, TFAM binds to mitochondrial DNA (mtDNA) and activates the transcription and replication of the mitochondrial genome, a crucial step in the generation of new organelles. TF, transcription factor.