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Mitofusin 2 Is Essential for IP3-Mediated SR/Mitochondria Metabolic Feedback in Ventricular Myocytes

2019; Frontiers Media; Volume: 10; Linguagem: Inglês

10.3389/fphys.2019.00733

1664-042X

Lea K. Seidlmayer, Christine Mages, Annette Berbner, Petra Eder-Negrin, Paula Arias-Loza, Mathias Kaspar, Moshi Song, Gerald W. Dorn, Michael Kohlhaas, Stefan Frantz, Christoph Maack, Brenda Gerull, Elena N. Dedkova,

ATP Synthase and ATPases Research

Endothelin-1 (ET-1) and Angiotensin II (Ang II) are multifunctional peptide hormones which regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP3) by activating their membrane-bound receptors. We have previously demonstrated that IP3-mediated sarcoplasmic reticulum (SR) Ca2+ release results in mitochondrial Ca2+ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP3-mediated SR/mitochondrial feedback. As a model for disrupted mitochondrial/SR microdomains, cardiospecific tamoxifen-inducible mitofusin 2 (Mfn-2) knock out (KO) mice were used. Mfn-2 tethers SR to mitochondria in healthy cells. When the physical link between SR and mitochondria by Mfn-2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was severely impaired resulting in inability of the IP3-mediated SR Ca2+ release to induce ATP production in Mfn-2 KO mice. Our study demonstrates that in cardiomyocytes ET-1 signaling is required for maintaining normal cardiac function and bioenergetics. We further show that when the physical linkage between SR and mitochondria by Mfn-2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was severely impaired resulting in inability of the IP3-mediated SR Ca2+ release to induce ATP production. This finding further supports the importance of intact SR/mitochondria microdomains in cardiac myocytes.