Crosstalk between Mitochondrial and Sarcoplasmic Reticulum Ca2+ Cycling Modulates Cardiac Pacemaker Cell Automaticity

Abstract

Mitochondria dynamically buffer cytosolic Ca²⁺ in cardiac ventricular cells and this affects the Ca²⁺ load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca²⁺ releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na⁺-Ca²⁺ exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP). To determine if mitochondrial Ca²⁺ (Ca²⁺_m), cytosolic Ca²⁺ (Ca²⁺_c)-SR-Ca²⁺ crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity. Inhibition of mitochondrial Ca²⁺ influx into (Ru360) or Ca²⁺ efflux from (CGP-37157) decreased [Ca²⁺]_m to 80±8% control or increased [Ca²⁺]_m to 119±7% control, respectively. Concurrent with inhibition of mitochondrial Ca²⁺ influx or efflux, the SR Ca²⁺ load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively. Changes in total ensemble LCR Ca²⁺ signal were highly correlated with the change in the SR Ca²⁺ load (r² = 0.97). Changes in the spontaneous AP cycle length (Ru360, 111±1% control; CGP-37157, 89±2% control) in response to changes in [Ca²⁺]_m were predicted by concurrent changes in LCR period (r² = 0.84). A change in SANC Ca²⁺_m flux translates into a change in the AP firing rate by effecting changes in Ca²⁺_c and SR Ca²⁺ loading, which affects the characteristics of spontaneous SR Ca²⁺ release.