Sarcoplasmic reticulum-mitochondria communication; implications for cardiac arrhythmia

Abstract

Sudden cardiac death due to ventricular tachyarrhythmias remains the major cause of mortality in the world. Heart failure, diabetic cardiomyopathy, old age-related cardiac dysfunction and inherited disorders are associated with enhanced propensity to malignant cardiac arrhythmias. Both defective mitochondrial function and abnormal intracellular Ca²⁺ homeostasis have been established as the key contributing factors in the pathophysiology and arrhythmogenesis in these conditions. This article reviews current advances in understanding of bidirectional control of ryanodine receptor-mediated sarcoplasmic reticulum Ca²⁺ release and mitochondrial function, and how defects in crosstalk between these two organelles increase arrhythmic risk in cardiac disease.

Keywords: Calcium signaling; Cardiac arrhythmia; Mitochondria; Sarcoplasmic reticulum.

Figure 1.. Free mitochondrial matrix [Ca²⁺] dynamics in intact ventricular myocytes.

Free mitochondrial matrix [Ca²⁺] was monitored using a Leica SP8 Lightning laser scanning confocal system at 8 ms per frame at room temperature in a cultured rat ventricular myocyte adenovirally expressing red mtRCamp1h biosensor (Kd = 1.3 μM) [85,114]. Cytosolic Ca²⁺ transients were recorded using Fluo-3 AM as described in [9], and presented as F/F₀. Mito-[Ca²⁺] was estimated using following equation: Kd*(F-Fmin)/(Fmax-F). Fmin was fluorescence in the presence of 5 mM EGTA, and Fmax was fluorescence at 200 μM [Ca²⁺] in cell permeabilized with saponin. A. Superimposed representative traces of cytosolic Ca²⁺ transients and mito-[Ca²⁺] in a field-stimulated rat ventricular myocyte in the presence of 50 nM isoproterenol. Increase in stimulation frequency from 1 Hz to 2 Hz leads to an increase in mito-[Ca²⁺] due to slow removal kinetics. B. Enlarged superimposed traces from A demonstrate that mito-Ca²⁺ time to-peak is 5–10 fold slower than cytosolic Ca²⁺ transient time-to peak. C. The dependence of mito-[Ca²⁺] level upon stimulation frequency.

Figure 2.. Intracellular Ca²⁺ sources and mitochondrial subpopulations in adult ventricular myocytes.

Upon RyR2-mediated SR Ca²⁺ release, free [Ca²⁺] in the dyadic space increases from 200 nM to ≥200 μM, which leads to an increase in submembrane [Ca²⁺] to 20–40 μM. SR free-[Ca²⁺] reciprocally decreases from ~1 mM to 200–400 μM. The cytosolic [Ca²⁺] during SR Ca²⁺ release increases from basal 100 nM to 300 nM, and can reach 3–4 μM when myocytes are exposed to β-adrenergic stimulation. Under periodic stimulation, mito-[Ca²⁺] increases from 100–200 nM to 1 μM and up to 5 μM in the presence of β-agonists. In interfibrillar mitochondria, MCU complexes are situated at the end that faces the back of jSR cisternae. The theoretical estimate for jSR-mitochondria nanodomain [Ca²⁺] is 10–20 μM. Supporting experimental data is missing. NCLX is situated further from the jSR cisternae, which may underlie mito-[Ca²⁺] gradient. Subsarcolemmal mitochondria may be exposed to higher Ca²⁺ during Ca²⁺ transient due to higher submembrane [Ca²⁺] vs cytosolic [Ca²⁺], and more direct communication of RyR2 in corbular SR and mitochondrial VDAC. The exact free mito-[Ca²⁺] for this subpopulation remains unknown. During periodic pacing, perinuclear mitochondria accumulates [Ca²⁺] slower probably due to longer distances to RyR2 clusters. Stimulation of IP₃ receptors increases perinuclear mito-[Ca²⁺]. Whether interfibrillar and perinuclear mito-[Ca²⁺]s differ under certain conditions remains unknown. Figure created with BioRender.com.