Mitophagy in Heart Failure-A Selective Autophagic Degradation of Mitochondria

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2009-06-05

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INTRODUCTION: Cardiovascular disease is associated with declines in mitochondrial function. Autophagy is a lysosomal-dependent process through which cytoplasmic proteins and organelles can be degraded and has recently been shown to participate in remodeling of the myocardium in a variety of cardiac pathologies. Autophagy can be either non-selective or selective for damaged protein aggregates or organelles. Reactive oxygen species (ROS) generated in mitochondria causes mitochondrial permeability transition (MPT) and induces selective degradation of mitochondria (mitophagy). We hypothesized that mitophagy contributes to remodeling of the heart under severe oxidative stress. METHODS: Mice were subjected to hemodynamic overload by severe thoracic aortic constriction (sTAC). qPCR was used to measure the abundance of mtDNA relative to nuclear DNA. Changes in proteins and cardiac function were also assessed.

RESULTS: Decreases in mtDNA abundance were time dependent after sTAC (-47%񱷠at day 2, p<0.1; -73%񱰠at day 4, p<0.05) (n=2 each) and correlated with increased mortality (37% at day 2; 75% at day 4). The decline in mtDNA was greater in the basal septum (-88%񲬠p<0.01) than in the left ventricular free wall (- 42%񱵬 p<0.15) (n=4) day 8 post-sTAC. The basal septum is where we have observed the largest increases in autophagic activity and protein carbonylation, a ROS-mediated protein modification. Daily injections with cyclosporine (CsA), an inhibitor of both MPT and calcineurin, blunted load-induced mtDNA loss (-28%񲠷ith CsA vs -83%񱰠with vehicle treatment, p<0.01) (n=3) at 4 days post-sTAC. Furthermore, CsA improved survival at 4 days-post sTAC (40% mortality with CsA vs 75% with vehicle) (n=5-8). Mice with increased ROS generation due to a disruption of the cardiac isoform of the cytochrome-c oxidase subunit COXVIaH were more sensitive to pressure overload-induced loss of mtDNA and mitochondrial proteins.
CONCLUSION: MtDNA abundance declines in this model of load-induced heart failure and is associated with increased autophagic activity and ROS generation. Short-term application of CsA can blunt mtDNA loss and improve survival.

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