The basics of mitochondrial cAMP signalling: Where, when, why

Cytosolic cAMP signalling in live cells has been extensively investigated in the past, while only in the last decade the existence of an intramitochondrial autonomous cAMP homeostatic system began to emerge. Thanks to the development of novel tools to investigate cAMP dynamics and cAMP/PKA-dependent phosphorylation within the matrix and in other mitochondrial compartments, it is now possible to address directly and in intact living cells a series of questions that until now could be addressed only by indirect approaches, in isolated organelles or through subcellular fractionation studies. In this contribution we discuss the mechanisms that regulate cAMP dynamics at the surface and inside mitochondria, and its crosstalk with organelle Ca²⁺ handling. We then address a series of still unsolved questions, such as the intramitochondrial localization of key elements of the cAMP signaling toolkit, e.g., adenylate cyclases, phosphodiesterases, protein kinase A (PKA) and Epac. Finally, we discuss the evidence for and against the existence of an intramitochondrial PKA pool and the functional role of cAMP increases within the organelle matrix.