Mitochondrial Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes

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 (If) 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 Ca2+ 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.

• Publication year

  2018

• Venue

  PLoS ONE

• Publication date

  2018-07-12

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1371/journal.pone.0200448PMID 30001390PMCID 6042741
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• From two competing oscillators to one coupled-clock pacemaker cell system

  2015cited by this paper
• The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart.

  2015cited by this paper
• Potential effects of intrinsic heart pacemaker cell mechanisms on dysrhythmic cardiac action potential firing

  2015cited by this paper
• The mitochondrial Na+-Ca2+ exchanger, NCLX, regulates automaticity of HL-1 cardiomyocytes

  2013cited by this paper
• Modulation of Intracellular Calcium Waves and Triggered Activities by Mitochondrial Ca Flux in Mouse Cardiomyocytes

  2013cited by this paper
• Effects of mitochondrial uncoupling on Ca(2+) signaling during excitation-contraction coupling in atrial myocytes.

  2013cited by this paper
• Mitochondria and arrhythmias.

  2013cited by this paper
• Mechanisms of Altered Ca2+ Handling in Heart Failure

  2013cited by this paper
• Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes

  2013cited by this paper
• Crosstalk between Mitochondrial and Sarcoplasmic Reticulum Ca2+ Cycling Modulates Cardiac Pacemaker Cell Automaticity

  2012cited by this paper
• Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes

  2012cited by this paper
• Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice.

  2012cited by this paper
• CaMKII determines mitochondrial stress responses in heart

  2012cited by this paper
• Rhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling.

  2011cited by this paper
• Ischemic ventricular arrhythmias: experimental models and their clinical relevance.

  2011cited by this paper
• A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter

  2011cited by this paper
• High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents.

  2011cited by this paper
• Automaticity in acute ischemia: bifurcation analysis of a human ventricular model.

  2011cited by this paper
• Elevated Cytosolic Na+ Increases Mitochondrial Formation of Reactive Oxygen Species in Failing Cardiac Myocytes

  2010cited by this paper
• MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake

  2010cited by this paper
• Cell biology: A sensor for calcium uptake

  2010cited by this paper
• Proarrhythmic risk of embryonic stem cell-derived cardiomyocyte transplantation in infarcted myocardium.

  2010cited by this paper
• Control of Ca2+ release by action potential configuration in normal and failing murine cardiomyocytes.

  2010cited by this paper
• Rhythmic Fluctuations in the Concentration of Intracellular Mg2+ in Association with Spontaneous Rhythmic Contraction in Cultured Cardiac Myocytes

  2008cited by this paper
• Inositol‐1,4,5‐trisphosphate‐mediated spontaneous activity in mouse embryonic stem cell‐derived cardiomyocytes

  2007cited by this paper
• New insights into pacemaker activity: promoting understanding of sick sinus syndrome.

  2007cited by this paper
• FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation.

  2006cited by this paper
• Elevated Cytosolic Na+ Decreases Mitochondrial Ca2+ Uptake During Excitation–Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes

  2006cited by this paper
• Mitochondrial membrane potential modulates regulation of mitochondrial Ca2+ in rat ventricular myocytes.

  2005cited by this paper
• Mitochondrial Ca2+ homeostasis in health and disease.

  2004cited by this paper
• Mitochondrial Ca 2+ homeostasis in health and disease

  2004cited by this paper
• Characterization and regulation of T-type Ca2+ channels in embryonic stem cell-derived cardiomyocytes.

  2003cited by this paper
• Characterization and regulation of T-type Ca 2 channels in embryonic stem cell-derived cardiomyocytes

  2003cited by this paper
• The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

  2002cited by this paper
• Current-dependent Block of Rabbit Sino-Atrial Node If Channels by Ivabradine

  2002cited by this paper
• Stem Cell-Derived Cardiomyocytes Demonstrate Arrhythmic Potential

  2002cited by this paper
• Embryonic stem cells as a model to study cardiac, skeletal muscle, and vascular smooth muscle cell differentiation.

  2002cited by this paper
• The role of inositol 1,4,5‐trisphosphate receptors in Ca2+ signalling and the generation of arrhythmias in rat atrial myocytes

  2002cited by this paper
• Targeted inactivation of the sodium‐calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization

  2001cited by this paper
• Cardiac Na(+)-Ca(2+) exchange: molecular and pharmacological aspects.

  2001cited by this paper
• Cardiac Na+-Ca2+ Exchange Molecular and Pharmacological Aspects

  2001cited by this paper
• Sinoatrial Nodal Cell Ryanodine Receptor and Na + -Ca 2+ Exchanger: Molecular Partners in Pacemaker Regulation

  2001cited by this paper
• Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells

  2000cited by this paper
• Cardiac myocyte calcium transport in phospholamban knockout mouse: relaxation and endogenous CaMKII effects.

  1998cited by this paper
• Oxygen-bridged Dinuclear Ruthenium Amine Complex Specifically Inhibits Ca2+ Uptake into Mitochondria in Vitroand in Situ in Single Cardiac Myocytes*

  1998cited by this paper
• Cardiac myocyte calcium transport in phospholamban knockout mouse: relaxation and endogenous CaMKII effects.

  1998cited by this paper
• Dual activation of adenosine A1 and A3 receptors mediates preconditioning of isolated cardiac myocytes.

  1997cited by this paper
• Hyperpolarization-activated inward current in embryonic chick cardiac myocytes: developmental changes and modulation by isoproterenol and carbachol.

  1993cited by this paper
• Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157.

  1993cited by this paper

• The Role of Advanced Glycation End Products in the Etiology of Premature Ventricular Contractions.

  2025cites this paper
• Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation

  2025cites this paper
• Lysosomal Ca2+ Release Through TRPML1 Governs Ventricular Arrhythmia After Myocardial Infarction

  2025cites this paper
• Programmed spontaneously beating cardiomyocytes in regenerative cardiology.

  2024cites this paper
• Regulation of SR and mitochondrial Ca2+ signaling by L-type Ca2+ channels and Na/Ca exchanger in hiPSC-CMs.

  2024cites this paper
• Lysosomal Ca2+ flux modulates automaticity in ventricular cardiomyocytes and correlates with arrhythmic risk

  2023cites this paper
• Cardiac sympathetic denervation prevents sudden cardiac arrest and improves cardiac function by enhancing mitochondrial-antioxidant capacity

  2023cites this paper
• miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure.

  2023cites this paper
• Parkin Insufficiency Accentuates High-Fat Diet–Induced Cardiac Remodeling and Contractile Dysfunction Through VDAC1-Mediated Mitochondrial Ca2+ Overload

  2022cites this paper
• Mitochondrial Ca2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

  2022cites this paper
• Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts

  2021cites this paper
• Sarcoplasmic reticulum-mitochondria communication; implications for cardiac arrhythmia.

  2021cites this paper
• FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

  2020cites this paper
• IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

  2020cites this paper
• Ca2+ signaling of human pluripotent stem cells-derived cardiomyocytes as compared to adult mammalian cardiomyocytes.

  2020cites this paper
• Effect of inositol 1, 4, 5-trisphosphate receptor dependent Ca2+ release in atrial fibrillation

  2020cites this paper
• Magnesium supplementation improves diabetic mitochondrial and cardiac diastolic function.

  2019cites this paper
• Role of mitochondrial Ca2+ homeostasis in cardiac muscles.

  2019cites this paper
• Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease

  2019cites this paper
• Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship.

  2019cites this paper
• Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

  2019cites this paper