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Mitochondrial Ca flux modulates spontaneous electrical activity in ventricular cardiomyocytes

PLoS ONE, ISSN: 1932-6203, Vol: 13, Issue: 7, Page: e0200448
2018
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Introduction Ca release from sarcoplasmic reticulum (SR) is known to contribute to automaticity via the cytoplasmic Na-Ca exchanger (NCX). Mitochondria participate in Ca cycling. We studied the role of mitochondrial Ca flux in ventricular spontaneous electrical activity. Methods Spontaneously contracting mouse embryonic stem cells (ESC)-derived ventricular cardiomyocytes (CMs) were differentiated from wild type and ryanodine receptor type 2 (RYR2) knockout mouse ESCs and differentiated for 19–21 days. Automaticity was also observed in human induced pluripotent stem cell (hiPSC)-derived ventricular CMs differentiated for 30 days, and acute isolated adult mouse ventricular cells in ischemic simulated buffer. Action potentials (APs) were recorded by perforated whole cell current-clamp. Cytoplasmic and mitochondrial Ca transients were determined by fluorescent imaging. Results In mouse ESC-derived ventricular CMs, spontaneous beating was dependent on the L-type Ca channel, cytoplasmic NCX and mitochondrial NCX. Spontaneous beating was modulated by SR Ca release from RYR2 or inositol trisphosphate receptors (IPR), the pacemaker current (I) and mitochondrial Ca uptake by the mitochondrial Ca uniporter (MCU). In RYR2 knockout mouse ESC-derived ventricular CMs, mitochondrial Ca flux influenced spontaneous beating independently of the SR Ca release from RYR2, and the mitochondrial effect was dependent on IPR SR Ca release. Depolarization of mitochondria and preservation of ATP could terminate spontaneous beating. A contribution of mitochondrial Ca flux to automaticity was confirmed in hiPSC-derived ventricular CMs and ischemic adult mouse ventricular CMs, confirming the findings across species and cell maturity levels. Conclusions Mitochondrial and sarcolemma NCX fluxes are required for ventricular automaticity. Mitochondrial Ca uptake plays a modulatory role. Mitochondrial Ca uptake through MCU is influenced by IPR-dependent SR Ca release.

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