cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.

The oxidative phosphorylation (OXPHOS) system couples the transfer of electrons to oxygen with pumping of protons across the inner mitochondrial membrane, ensuring the ATP production. Evidence suggests that respiratory chain complexes may also assemble into supramolecular structures, called supercomplexes (SCs). The SCs appear to increase the efficiency/capacity of OXPHOS and reduce the reactive oxygen species (ROS) production, especially that which is produced by complex I.

cAMP/Ca2+ response element-binding protein plays a central role in the biogenesis of respiratory chain proteins in mammalian cells.

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.

cAMP-dependent protein kinase regulates post-translational processing and expression of complex I subunits in mammalian cells.

Work is presented on the role of cAMP-dependent protein phosphorylation in post-translational processing and biosynthesis of complex I subunits in mammalian cell cultures. PKA-mediated phosphorylation of the NDUFS4 subunit of complex I promotes in cell cultures in vivo import/maturation in mitochondria of the precursor of this protein. The import promotion appears to be associated with the observed cAMP-dependent stimulation of the catalytic activity of complex I.

cAMP response element-binding protein (CREB) is imported into mitochondria and promotes protein synthesis.

The cAMP response element-binding protein (CREB) is a ubiquitous transcription factor in the higher eukaryotes that, once phosphorylated, promotes transcription of cAMP response element-regulated genes. We have studied the mitochondrial import of CREB and its effect on the expression of mtDNA-encoded proteins. [(35)S]Methionine-labelled CREB, synthesized in vitro in the Rabbit Reticulocyte Lysate system using a construct of the human cDNA, was imported into the matrix of isolated rat liver mitochondria by a membrane potential and TOM complex-dependent process.