In mammalian cells, promotion of mitochondrial biogenesis by various agents involves cAMP and Ca(2+)-mediated signal transduction pathways. Recruitment of these pathways results in phosphorylation by cAMP and Ca(2+)-dependent protein kinases of cAMP/Ca(2+) response element-binding protein (CREB). Phosphorylation of CREB, bound to transcriptional complexes of target genes, activates a down-stream cascade of transcriptional complexes, which involve in sequence, the nuclear factors TORCs, PGC-1, NRF1 and NRF2, and the mitochondrial factor mitochondrial transcriptional factor A. CREB also binds directly to the D-loop of mitochondrial DNA and activates its expression. Activation of this network of transcriptional complexes results in concerted promotion of the expression of nuclear and mitochondrial genes encoding subunits of oxidative phosphorylation complexes.