**8. Conclusions**

marked insulin resistance and increased muscle protein degradation (Lorza-Gil et al., unpublished data). Therefore, toxic effects on insulin secreting cells in conjunction with impaired muscle insulin signaling may explain the new onset of diabetes reported in statin-treated subjects.

The cholesterol biosynthesis pathway generates several products including CoQ10 [213]. CoQ10 is an essential component of the electron transport chain where it acts as an electron carrier [214]. Ubiquinol, the reduced form of ubiquinone, when associated with proteins in the inner mitochondrial membrane, has an important function as a lipophilic antioxidant [215, 216]. CoQ10 also has additional functions such as regeneration of reduced intra- and extracellular forms of ascorbic acid and tocopherol (vitamin E) [217, 218], participation in redox processes associated with PTP opening [219], and regulation of muscle uncoupling proteins [220]. It is also known that the reduced form of ubiquinone occurs in all cellular membranes [221–223] as well as in serum lipoproteins and DNA, protecting them from oxidative damage [224]. CoQ10 content is larger in tissues such as cardiac and skeletal muscles that have high energy demand [223]. Therefore, decreased synthesis of ubiquinone may result in two harmful conditions: (a) insufficient rates of mitochondrial ATP synthesis [225] and (b)

Some studies have proposed that statin-induced mitotoxicity may be mediated by diminished CoQ10 content with consequent impairment of mitochondrial respiration [111, 226–234]. On the other hand, our group has provided evidence that under our experimental conditions, the reduction of mitochondrial respiration associated with CoQ10 depletion was mainly due to its free radical scavenging action rather than its electron carrier function. Indeed, it has been demonstrated that incubation of permeabilized rat soleus muscle with simvastatin inhibited both ADP and FCCP-stimulated oxygen consumption supported by complex I or II substrates.

cantly increased. Under these conditions, all of the following compounds, including mevalonate,

depletion. Thus, independent of CoQ10 levels, L-carnitine prevented the toxic effects of simvastatin. This allows for the conclusion that L-carnitine antioxidant action prevailed in the protection against simvastatin-induced respiratory inhibition [49]. Therefore, it can be concluded that CoQ10 also acted as a free radical scavenger in this mechanism. Accordingly, Kettawan and coworkers previously demonstrated that a decrease in ubiquinone levels in serum, liver, and heart in mice undergoing simvastatin treatment increased lipoperoxidation. Simvastatin also reduced NADPH-CoQ reductase activity, whereas the co-administration of CoQ10 and simvastatin to mice diminished these deleterious effects [235]. Another study revealed that simvastatin reduced mitochondrial CoQ10 levels associated with DNA oxidative damage and reduced ATP synthesis followed by cell death in hepatocytes (HepG2). All of these alterations were reversed by CoQ10 supplementation [236]. Furthermore, it was recently shown that CoQ10 supplementation improved respiratory control in liver mitochondria isolated from rats treated with high

O2

O2

generation but only mevalonate prevented CoQ10

content was signifi-

**7. Antioxidant supplement and statins toxicity**

396 Mitochondrial Diseases

decreased mitochondrial antioxidant capacity [49].

CoQ10, or L-carnitine protected against H<sup>2</sup>

Additionally, ubiquinone content was diminished by 40% and the H<sup>2</sup>

Cardiovascular benefits of statins therapy are undoubted and appear to be present across diverse demographic and clinical groups. However, the side effects may affect a minority of patients. In this review, we addressed the cellular and molecular mechanisms related to statin side effects. Mitochondrial oxidative stress seems to be the main cause of toxicity in statin sensitive tissues (**Figure 1**). The levels and consequences of mitochondrial oxidative stress seem to be more deleterious in skeletal muscle. This effect is secondary to: (a) inhibition of electrons flow at the levels of respiratory complexes I, II, and III, and (b) decrease in the levels of CoQ10 due to inhibition of the mevalonate pathway. In association with mitochondrial Ca2+ overload due to increased cytosolic free Ca2+ concentrations, the PTP may open and trigger cell death. *In vitro* experiments provide evidence that this can be blocked in a concerted manner by L-carnitine plus the membrane stabilizer piracetam. Experiments performed with muscle biopsies taken from hypercholesterolemic mice, chronically treated with pravastatin, show that either CoQ10 or creatine can protect against statin-induced mitochondrial muscle toxicity both *in vitro* and *in vivo*. Statin treatment may also result in pro- or antioxidant actions depending on statin class (lipophilicity), dose, and patient's background. We suggest that mitochondrial oxidative stress caused by statin treatment may be a signal for cellular antioxidant system response (such as catalase upregulation) possibly explaining the alleged statin antioxidant properties. Together, the experimental evidence presented in this review suggests that statins' detrimental effects could be prevented by antioxidants administration such as CoQ10, L-carnitine, and creatine.

IP3

R Inositol 1,4,5-trisphosphate receptor

MPT Mitochondrial permeability transition

NNT Nicotinamide nucleotide transhydrogenase

VDAC Voltage-dependent anion-selective channel

, Estela Lorza-Gil<sup>2</sup>

Mitochondrial Oxidative Stress and Calcium-Dependent Permeability Transition are Key Players…

1 Faculty of Medical Sciences, Department of Clinical Pathology, UNICAMP, SP, Brazil 2 Institute of Biology, Department of Structural and Functional Biology, UNICAMP, SP,

[1] Brown MS, Goldstein JL. Receptor-mediated endocytosis: Insights from the lipoprotein receptor system. Proceedings of the National Academy of Sciences of the United States

[2] Vogt A. The genetics of familial hypercholesterolemia and emerging therapies. The

[3] Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. The New England

[4] Collins R, Armitage J, Parish S, Sleigh P, Peto R, HPSC Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet. 2003;**361**:2005-2016. DOI: 10.1016/S0140-6736(03)13636-7

Application of Clinical Genetics. 2015;**8**:27-36. DOI: 10.2147/TACG.S44315

Journal of Medicine. 1995;**333**:1301-1307. DOI: 10.1056/NEJM199511163332001

, Helena C.F. de Oliveira<sup>2</sup>

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

399

and

MCU Mitochondrial calcium uniporter

OMM Outer mitochondria membrane

SHR Spontaneous hypertensive rats

, Ana C. Marques<sup>1</sup>

\*Address all correspondence to: anibal@unicamp.br

PTP Permeability transition pore

ROS Reactive oxygen species

TSST Thioredoxin

\*

of America. 1974;**71**:788-792

**Author details**

Anibal E. Vercesi<sup>1</sup>

Brazil

**References**

Estela N.B. Busanello<sup>1</sup>
