Role of mitochondrial soluble adenylyl cyclase, phosphodiesterases and Epac in cardiac mitochondrial function and cell death

Abstract : CAMP is an important messenger in neurohormonal regulation of the heart. By activating its effectors, cAMP regulates many cellular functions such as gene expression, excitation-contraction coupling and cellular metabolism. In mammals, cAMP is produced by a family of adenylyl cyclase with various subcellular locations and membrane anchorage. The existence and role of cyclic nucleotide signaling in mitochondria has been postulated, but has not yet been demonstrated. Moreover, its implication in the regulation of cell death is still unknown. In this thesis, we demonstrated the local expression of several actors of cAMP signaling within cardiac mitochondria, namely a truncated form of soluble AC (sACt) and the exchange protein directly activated by cAMP 1 (Epac1) and showed a protective role for sACt against cell death, apoptosis as well as necrosis, in primary cardiomyocytes. Upon stimulation with bicarbonate (HCO3-) and Ca2+, sACt produces cAMP, which in turn stimulates oxygen consumption, increased the mitochondrial membrane potential (∆Ψm) and ATP production. cAMP is rate-limiting for matrix Ca2+ entry via the mitochondrial calcium uniporter (MCU) and, as a consequence, prevented mitochondrial permeability transition (MPT). In addition, in mitochondria isolated from failing rat hearts, stimulation of the mitochondrial cAMP pathway by HCO3- rescued the sensitization of mitochondria to Ca2+-induced MPT. We also found that PDE2, 3 and 4 families are located in cardiac mitochondria. They form a local signaling pathway with soluble AC in the matrix, which regulates cardiac mitochondrial functions. Thus, our study identifies a link between mitochondrial cAMP, mitochondrial metabolism, some PDEs and cell death in the heart, which is independent of cytosolic cAMP signaling. This might constitute a novel cardioprotective mechanism through mitochondrial function preservation in pathophysiological conditions.
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Zhenyu Wang. Role of mitochondrial soluble adenylyl cyclase, phosphodiesterases and Epac in cardiac mitochondrial function and cell death. Cellular Biology. Université Paris-Saclay, 2016. English. ⟨NNT : 2016SACLS186⟩. ⟨tel-02181158⟩

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