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

DOI: 10.5772/intechopen.71610

Estela N.B. Busanello, Ana C. Marques, Estela Lorza-Gil, Helena C.F. de Oliveira and Anibal E. Vercesi Estela N.B. Busanello, Ana C. Marques, Estela Lorza-Gil, Helena C.F. de Oliveira and Anibal E. Vercesi Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71610

#### **Abstract**

[129] Chen H, Chan DC. Mitochondrial dynamics – fusion, fission, movement, and mitophagy – in neurodegenerative diseases. Human Molecular Genetics. 2009;**18**:R169-R176

[130] Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nature

[131] Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial func-

[132] Guerri C, Pascual M. Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. Alcohol. 2010;**44**:15-26

Reviews. Molecular Cell Biology. 2007;**8**:870-879

384 Mitochondrial Diseases

tion. Free Radical Biology & Medicine. 2015;**88**:179-188

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 signal for cellular antioxidant system responses such as catalase upregulation, possibly explaining 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.

**Keywords:** statins adverse effects, statins pleiotropic effects, reactive oxygen species (ROS), mitochondrial permeability transition, antioxidants
