Mitochondrial Oxidative Stress and Calcium-Dependent Permeability Transition are Key Players in the Mechanisms of Statins-Associated Side Effects

Statins are cholesterol-lowering medicines utilized worldwide and are associated with reduced risk of cardiovascular mortality and events. However, 0.5–10% of patients suffer from adverse effects especially on skeletal muscle. Recently, new onset of diabetes has been reported in subjects on statin therapy. Pro- and anti-oxidant effects of statins have been reported, thus fostering a debate. Previously reported data provide evidence that statins induce alterations in intracellular calcium homeostasis and mitochondrial dysfunctions that can be counteracted by antioxidants (e.g., CoQ10, creatine, and L-carnitine). Therefore, we have proposed that statin-induced inhibition of mitochondrial respiration leads to oxidative stress that opens a calcium-dependent permeability transition pore, an event that may lead to cell death. In addition, mitochondrial oxidative stress caused by statin treatment may be a sig nal for cellular antioxidant system responses such as catalase upregulation, possibly explain - ing the alleged statins’ antioxidant properties. Muscle mitochondrial dysfunction induced by statin treatment may be associated with the peripheral insulin resistance and may explain statins-induced new onset of diabetes. Together, the data presented in this review suggest that the statins’ detrimental effects can be prevented by co-administration of antioxidants . Thus, mitochondria uptake the excessive cytosolic Ca 2+ via VDAC and MCU channels, leading to its accumulation in mitochondrial matrix. Ca 2+ binds to membrane sites exposing specific buried thiols to the oxidants and also impairs mitochondrial respiration, increasing O 2 . - formation. The association of ROS and mitochondrial Ca 2+ overload, PTP may open and trigger cell death. In addition, a decrease in the levels of CoQ10 that acts as an electron carrier and antioxidant also occurs due to inhibition of the mevalonate pathway by statins. The antioxidants CoQ10, L-carnitine and creatine prevent PTP opening induced by statins .