Abstract 798: Ca2+ Sparks are Modulated by the Mitochondrial Energy State
Mitochondria produce reactive oxygen species (ROS) but are also a target of oxidative stress that can induce rapid oscillations of mitochondrial inner membrane potential (ΔΨ m). The proximity of mitochondria to SR Ca2+ release sites suggests that the mitochondrial energy state will determine the local redox and energetic status of the Ca2+ handling subsystem. Because ryanodine receptors, SERCA, and L-type Ca2+ channels are all sensitive to ATP, Mg2+ and thiol oxidation, we investigated whether laser flash-triggered mitochondrial ΔΨm oscillations influence resting Ca2+ spark frequency in fluo-4 + TMRE-loaded cardiomyocytes using two-photon microscopy to monitorΔΨm, cytosolic [Ca 2+], and [NADH]. The correlation between resting Ca2+ spark frequency and ΔΨm was analyzed over several cycles of ΔΨm oscillation in each cell. Notably, Ca2+ spark frequency increased with ΔΨm depolarization and decreased withΔΨm repolarization, indicative of close coupling between energetics and Ca2+ cycling (See Figure⇓). Moreover, spontaneous Ca2+ waves were often observed when mitochondria were depolarized but not whenΔΨm recovered. There were no significant effects on Ca2+ spark durations or rise times. In conclusion, the results show that stress-induced mitochondrial depolarization (involving NADH oxidation, ROS release, and depletion of glutathione) leads to increased Ca2+ spark frequency, most likely as a result of modification of the local redox status near the dyad. These findings provide important insights into the connection between metabolism and Ca2+ cycling in the heart with relevance to the mechanism of contractile and electrical dysfunction in cardiac disease states.