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Review
. 2021 Feb 22;10(2):473.
doi: 10.3390/cells10020473.

Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Muhammad Aslam  1   2   3 , Yury Ladilov  4
Affiliations
Review

Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Muhammad Aslam et al. Cells. .

Abstract

In contrast to the traditional view of mitochondria being solely a source of cellular energy, e.g., the "powerhouse" of the cell, mitochondria are now known to be key regulators of numerous cellular processes. Accordingly, disturbance of mitochondrial homeostasis is a basic mechanism in several pathologies. Emerging data demonstrate that 3'-5'-cyclic adenosine monophosphate (cAMP) signalling plays a key role in mitochondrial biology and homeostasis. Mitochondria are equipped with an endogenous cAMP synthesis system involving soluble adenylyl cyclase (sAC), which localizes in the mitochondrial matrix and regulates mitochondrial function. Furthermore, sAC localized at the outer mitochondrial membrane contributes significantly to mitochondrial biology. Disturbance of the sAC-dependent cAMP pools within mitochondria leads to mitochondrial dysfunction and pathology. In this review, we discuss the available data concerning the role of sAC in regulating mitochondrial biology in relation to diseases.

Keywords: EPAC; OXPHOS; PKA; apoptosis; cAMP; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; soluble adenylyl cyclase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic presentation of the effects of sAC-signalling on mitochondrial biology. Intramitochondrial sAC-signalling activates OXPHOS leading to ATP production. Under various stresses, extramitochondrial sAC–PKA axis promotes the recruitment of pro-apoptotic Bax to mitochondria and induces cytochrome c release leading to apoptosis. Furthermore, extramitochondrial sAC–PKA axis supports the removal of defective mitochondria (Mitophagy) by inducing recruitment of V-ATPase to lysosomes. Moreover, extramitochondrial sAC-signalling inhibits mitochondrial biogenesis via a still unknown mechanism. The extramitochondrial PKA and EPAC regulate mitochondrial dynamics and may be activated by the sAC-derived cAMP pool. AMP: Adenosine monophosphate; ATP: Adenosine 5′-triphosphate; cAMP: cyclic AMP; EPAC: Exchange protein directly activated by cAMP; Drp1: Dynamin-related protein 1; OXPHOS: oxidative phosphorylation; PDE2A: Phosphodiesterase 2A; PKA: Protein kinase A; sAC: soluble adenylyl cyclase; V-ATPase: Vacuolar-ATPase.
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