Three major pathways in the activation of mitochondrial biogenesis during aerobic work and/or energy limitation. These are: 1) intracellular calcium release, particularly in contractile tissues, which activates calcium/calmodulin kinase II (CaMKII) and cAMP-responsive element binding protein 1 (CREB1); 2) the NAD+/NADH ratio, which activates sirtuin-1 (SIRT1) causing deacetylation of peroxisome proliferator-activated receptor gamma co-activator 1- PGC-1 , and 3) a high AMP/ATP ratio, which activates AMP-activated kinase (AMPK), allowing phosphorylation of PGC-1 . PGC-1 co-activates nuclear respiratory factor-1 (NRF-1) and other transcription factors involved in mitochondrial biogenesis. Other abbreviations are NAMPT, nicotinamide phosphoribosyltransferase; CaMKK, calcium/calmodulin-dependent protein kinase kinase 2; ERR , estrogen-related receptor alpha; GABPA, GA binding protein alpha; Polg, DNA-directed polymerase gamma; Tfam, mitochondrial transcription factor A.