FIG. 8.

Proposed mechanism for statin-mediated cardioprotection. Statins are able to afford cardioprotection through an unknown mechanism beyond their ability to lower circulating levels of plasma cholesterol. Our findings elucidate this pathway and provide evidence for the first time that statin-mediated cardioprotection involves triggering mitophagy in the heart. Here we propose a mechanism by which statins promote cardiac mitophagy, which is essential for its protective effect: (1) Depletion of mevalonate (via inhibition of HMG-CoA reductase) attenuates Akt/mTOR signaling. (2) Diminished Akt/mTOR signaling relieves the inhibition of ULK1 resulting in increased macroautophagy. (3) Depletion of mevalonate results in loss of coenzyme Q₁₀, thereby impairing the ability of mitochondria to maintain their membrane potential. Autophagy targeting machinery is recruited to depolarized mitochondria. This mitophagy machinery includes (but is not limited to) Parkin and p62/SQSTM1. These elements of statin treatment set the stage for promoting mitophagy in the heart. (4) Increased mitophagy confers cardioprotection against I/R injury. HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; I/R, ischemia/reperfusion.