Enhancing autophagy reduces aberrant Ca2+ homeostasis in aging rabbit hearts and arrhythmogenesis
Aim: Aging is associated with an increased incidence of malignant tachyarrhythmia, which can cause sudden cardiac death. We found that thiol oxidation by mitochondria-derived ROS (mitoROS) of ryanodine-receptors (RyR2s), contributes to a defective Ca2+-homeostasis within cardiomyocytes from aging rabbit heart. The mechanisms that cause the increased mito-ROS levels in aging hearts are not well understood. We test the hypothesis here that an age-associated decrease of autophagy leads to increased mito-ROS and pro-arrhythmic disruptions in Ca2+ hhomeostasis.
Methods and Results Ventricular tissue from aged rabbits showed significant downregulation of mitochondrial autophagy proteins compared to tissues from young controls. Chloroquine blocking autophagy increased ROS production and mito-ROS in HL-1 cells. Chloroquine treatment also reduced the mitochondrial membrane potential of HL-1 to 50% of that in controls. The blocking of autophagy resulted in a significant increase in oxidation RyR2, which led to an increased propensity for pro-arrhythmic Ca2+ release when stimulated with b-adrenergic stimuli. Mito-TEMPO, a mitooxidant scavenger, was used to eliminate the aberrant Ca2+ releases. The autophagy enhancer Torin1 overexpression and ATG7 expression reduced the rate at which mito-ROS was produced and restored both Dpsm, and defective Ca2+ management in CMs derived aged rabbit hearts.
Conclusion: Reduced autophagy in the heart of aging patients is a major contributor to increased mito ROS production. Our data suggest that autophagy promotion may reduce pathologic Mito-ROS in normal aging, and reduce pro-arrhythmic Ca2+ spontaneous release via oxidized R2s.