Mitochondrial Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes

被引：20

作者：

Xie, An ^{[1
]}

Zhou, Anyu ^{[1
]}

Liu, Hong ^{[1
]}

Shi, Guangbin ^{[1
]}

Liu, Man ^{[1
]}

Boheler, Kenneth R. ^{[2
]}

Dudley, Samuel C., Jr. ^{[1
]}

机构：

[1] Univ Minnesota, Dept Med, Lillehei Heart Inst, Box 736 UMHC, Minneapolis, MN 55455 USA

[2] Univ Hong Kong, LKS Fac Med, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China

来源：

PLOS ONE | 2018年 / 13卷 / 07期

关键词：

CELL-DERIVED CARDIOMYOCYTES; CARDIAC MYOCYTES; RYANODINE RECEPTOR; CALCIUM UNIPORTER; ATRIAL MYOCYTES; HEART; ARRHYTHMIAS; CONTRIBUTES; MECHANISMS; EXCHANGER;

D O I：

10.1371/journal.pone.0200448

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Introduction Ca2+ release from sarcoplasmic reticulum (SR) is known to contribute to automaticity via the cytoplasmic Na+-Ca2+ exchanger (NCX). Mitochondria participate in Ca2+ cycling. We studied the role of mitochondrial Ca2+ 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 Ca2+ transients were determined by fluorescent imaging. Results In mouse ESC-derived ventricular CMs, spontaneous beating was dependent on the L-type Ca2+ channel, cytoplasmic NCX and mitochondrial NCX. Spontaneous beating was modulated by SR Ca2+ release from RYR2 or inositol trisphosphate receptors (IP3R), the pacemaker current (I-f) and mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU). In RYR2 knockout mouse ESC-derived ventricular CMs, mitochondrial Ca2+ flux influenced spontaneous beating independently of the SR Ca(2+ )release from RYR2, and the mitochondrial effect was dependent on IP3R SR Ca2+ release. Depolarization of mitochondria and preservation of ATP could terminate spontaneous beating. A contribution of mitochondrial Ca2+ 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 Ca2+ uptake plays a modulatory role. Mitochondrial Ca2+ uptake through MCU is influenced by IP3R-dependent SR Ca2+ release.

引用

页数：17

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