Mitochondrial cAMP-PKA signaling: What do we really know?

Mitochondria are key organelles for cellular homeostasis. They generate the most part of ATP that is used by cells through oxidative phosphorylation. They also produce reactive oxygen species, neurotransmitters and other signaling molecules. They are important for calcium homeostasis and apoptosis. Considering the role of this organelle, it is not surprising that most mitochondrial dysfunctions are linked to the development of pathologies. Various mechanisms adjust mitochondrial activity according to physiological needs. The cAMP-PKA signaling emerged in recent years as a direct and powerful mean to regulate mitochondrial functions. Multiple evidence demonstrates that such pathway can be triggered from cytosol or directly within mitochondria. Notably, specific anchor proteins target PKA to mitochondria whereas enzymes necessary for generation and degradation of cAMP are found directly in these organelles. Mitochondrial PKA targets proteins localized in different compartments of mitochondria, and related to various functions. Alterations of mitochondrial cAMP-PKA signaling affect the development of several physiopathological conditions, including neurodegenerative diseases. It is however difficult to discriminate between the effects of cAMP-PKA signaling triggered from cytosol or directly in mitochondria. The specific roles of PKA localized in different mitochondrial compartments are also not completely understood. The aim of this work is to review the role of cAMP-PKA signaling in mitochondrial (patho)physiology.