**1. Introduction**

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by the presence of very high levels of low-density lipoprotein cholesterol (LDLc) in the blood stream

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

since birth. This cholesterol disorder was first described in the 1960s, and the existence of a mutated LDL receptor (LDLr) in FH patients was later discovered by Brown and Goldstein [1]. They observed that FH fibroblasts did not specifically bind and internalize LDL when compared with normal fibroblasts; that finding was the beginning of decades of work and discoveries concerning cholesterol metabolism regulation that led the pair to Nobel Prize award in 1985. Although the homozygous mutants for LDLr have an early cardiac death in the first or second decade of life, heterozygous FH patients usually do not present any early severe symptoms. The lack of diagnosis and treatment may have severe consequences considering the lifetime exposure to high LDLc concentrations. Increased LDLc levels are a well-established independent risk factor for cardiovascular diseases [2], and lowering LDL serum levels remains the primary treatment target in hypercholesterolemia [3, 4] that is undertaken in order to prevent and reduce cardiovascular and coronary heart diseases [5, 6].

Ca2+-dependent permeability transition underlie statins toxicity. The impact on cell or tissue pathophysiology will depend on the intensity of statins' effects on mitochondria. In this chapter, we review the literature data on the statins effects on mitochondrial functions and consequent

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

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

387

Mitochondria participation in the process of statin toxicity adds to the numerous roles of these organelles in cell pathophysiology [23, 24]. Considering that statin-mediated mitochondrial dysfunctions include many aspects of mitochondrial physiology such as inhibition of respiration, depletion of ubiquinone, redox imbalance, opening of the mitochondrial permeability transition pore (PTP) and disruption of energy conservation, we next outline some of these mitochondrial

During the last several decades, mitochondria have emerged as the center of attention in processes of cell signaling, cell injury, and cell death [25, 26]. According to the concept of coupling between respiration and oxidative phosphorylation through a transmembrane proton electrochemical potential that was introduced by Peter Mitchell [27], it is not difficult to understand that any condition that interferes with the ability to sustain the inner membrane proton potential leads to mitochondrial dysfunction [28]. In addition, the continuous oxygen reduction by the mitochondrial electron transport chain to build up the transmembrane proton gradient also generates a well-regulated amount of superoxide [23, 29]. Therefore, mitochondria have developed a complex antioxidant defense system composed of Mn-superoxide dismutase that con-

verts the superoxide radical generated during respiration into hydrogen peroxide (H<sup>2</sup>

toxicity may also include the participation of mitochondrial generated ROS [47–49].

is then reduced to water by glutathione and thioredoxin peroxidase or catalase [30]. Oxidized glutathione (GSSG) and thioredoxin (TSST) generated by peroxidases are converted to their reduced forms by glutathione and thioredoxin reductases, using NADPH as reducing power.

ent in the inner mitochondrial membrane [31–33]. Therefore mitochondria redox state is tightly regulated and connected with whole cell redox balance [34–36]. Furthermore, it is now generally accepted that superoxide as well as other forms of ROS can function as a signal for either adaptation or maladaptation to stress conditions [35]. In this regard, mitochondrial ROS generation leads to a nonlinear dose-response relationship called mitohormesis. In mitohormesis, high reactive oxygen concentrations exert devastating and irreversible effects on cell function and structures, whereas low concentrations may be associated with protective effects due to activation of cellular defense mechanisms [37, 38]. In fact, at progressively increasing physiological levels, ROS may successively regulate cellular processes such as proliferation and differentiation, activate adaptive programs such as transcriptional upregulation of antioxidant genes, and at higher levels, ROS may be a signal for senescence and regulated cell death [35]. In addition to the physiological processes, it seems that mitochondrial oxidative stress is responsible for the development and progression of a series of diseases such as cancer, diabetes, inflammatory diseases, hypertension, neurodegenerative and ischemia-related diseases, and aging [39–46]. Statin

, in a reaction catalyzed by NADP transhydrogenase that is pres-

O2 ). H<sup>2</sup> O2

**1.1. Mitochondrial energy-linked functions and reactive oxygen generation**

toxic tissue events.

properties in the following sections.

NADH then reduces NADP<sup>+</sup>

Cholesterol is synthesized from acetyl-CoA by a 30-step pathway, in which 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase is the rate-limiting enzyme, converting HMG-CoA into mevalonate. However, besides being involved in cholesterol synthesis, mevalonate is also a precursor for isoprenoids farnesyl diphosphate. Geranyl- (GPP), farnesyl- (FPP) and geranylgeranyl-pyrophosphate (GGPP) are precursors of sterols, dolichols, CoQ10, isoprenoids, and carotenoids. These important metabolites are involved in membrane structures, protein glycosylation and prenylation, electron transport in mitochondrial respiratory chain, and scavenging of ROS [7].

The first cholesterol-lowering agent, citrinin, was discovered in the 1970s. It was derived from fungal cultures, but this product was discontinued due to its hepatotoxicity [8, 9]. After this, another fungal-derived compound called compactin was purified and tested in rats; however, it failed to reduce plasma cholesterol because it had the rebound effect of inducing HMG-CoA reductase activity a few hours after administration [10]. At the end of the 1970s, a very potent compound chemically similar to compactin was synthesized based on independent studies from Endo and Alberts [11, 12], and after several trials, this potent compound, lovastatin, was approved and commercially available in 1986 [13]. Presently, there are seven natural (fungal-derived) or synthetic statins that are commercially available; this group consists of three hydrophilic (pravastatin, rosuvastatin, and pitavastatin) and four lipophilic (lovastatin, simvastatin, fluvastatin, and atorvastatin) [14–16]. Cerivastatin was approved by the Food and Drug Administration in 1998, but it was removed from the market in 2001 after reports of fatal rhabdomyolysis [17].

Statins are one of the most successful drugs for reducing cardiovascular diseases. High-intensity statins treatment is associated with the greatest reduction in mortality [18]. In addition to lowering plasma cholesterol, various studies have reported that statins have pleiotropic effects such as antioxidant, anti-inflammatory, and anti-tumorigenesis. Regarding statins redox effects, some groups have demonstrated protective roles of these compounds against cell oxidative damage [19, 20], whereas others have reinforced their toxic effects [21, 22]. Despite these discrepancies in these results over the last decade, accumulated data have indicated that alterations in mitochondrial energy-linked functions such as respiration, oxidative phosphorylation, redox state, Ca2+-dependent permeability transition underlie statins toxicity. The impact on cell or tissue pathophysiology will depend on the intensity of statins' effects on mitochondria. In this chapter, we review the literature data on the statins effects on mitochondrial functions and consequent toxic tissue events.

#### **1.1. Mitochondrial energy-linked functions and reactive oxygen generation**

since birth. This cholesterol disorder was first described in the 1960s, and the existence of a mutated LDL receptor (LDLr) in FH patients was later discovered by Brown and Goldstein [1]. They observed that FH fibroblasts did not specifically bind and internalize LDL when compared with normal fibroblasts; that finding was the beginning of decades of work and discoveries concerning cholesterol metabolism regulation that led the pair to Nobel Prize award in 1985. Although the homozygous mutants for LDLr have an early cardiac death in the first or second decade of life, heterozygous FH patients usually do not present any early severe symptoms. The lack of diagnosis and treatment may have severe consequences considering the lifetime exposure to high LDLc concentrations. Increased LDLc levels are a well-established independent risk factor for cardiovascular diseases [2], and lowering LDL serum levels remains the primary treatment target in hypercholesterolemia [3, 4] that is undertaken in order to prevent

Cholesterol is synthesized from acetyl-CoA by a 30-step pathway, in which 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase is the rate-limiting enzyme, converting HMG-CoA into mevalonate. However, besides being involved in cholesterol synthesis, mevalonate is also a precursor for isoprenoids farnesyl diphosphate. Geranyl- (GPP), farnesyl- (FPP) and geranylgeranyl-pyrophosphate (GGPP) are precursors of sterols, dolichols, CoQ10, isoprenoids, and carotenoids. These important metabolites are involved in membrane structures, protein glycosylation and prenylation, electron transport in mitochondrial respiratory chain, and

The first cholesterol-lowering agent, citrinin, was discovered in the 1970s. It was derived from fungal cultures, but this product was discontinued due to its hepatotoxicity [8, 9]. After this, another fungal-derived compound called compactin was purified and tested in rats; however, it failed to reduce plasma cholesterol because it had the rebound effect of inducing HMG-CoA reductase activity a few hours after administration [10]. At the end of the 1970s, a very potent compound chemically similar to compactin was synthesized based on independent studies from Endo and Alberts [11, 12], and after several trials, this potent compound, lovastatin, was approved and commercially available in 1986 [13]. Presently, there are seven natural (fungal-derived) or synthetic statins that are commercially available; this group consists of three hydrophilic (pravastatin, rosuvastatin, and pitavastatin) and four lipophilic (lovastatin, simvastatin, fluvastatin, and atorvastatin) [14–16]. Cerivastatin was approved by the Food and Drug Administration in 1998, but it was removed from the market in 2001 after reports of fatal

Statins are one of the most successful drugs for reducing cardiovascular diseases. High-intensity statins treatment is associated with the greatest reduction in mortality [18]. In addition to lowering plasma cholesterol, various studies have reported that statins have pleiotropic effects such as antioxidant, anti-inflammatory, and anti-tumorigenesis. Regarding statins redox effects, some groups have demonstrated protective roles of these compounds against cell oxidative damage [19, 20], whereas others have reinforced their toxic effects [21, 22]. Despite these discrepancies in these results over the last decade, accumulated data have indicated that alterations in mitochondrial energy-linked functions such as respiration, oxidative phosphorylation, redox state,

and reduce cardiovascular and coronary heart diseases [5, 6].

scavenging of ROS [7].

386 Mitochondrial Diseases

rhabdomyolysis [17].

Mitochondria participation in the process of statin toxicity adds to the numerous roles of these organelles in cell pathophysiology [23, 24]. Considering that statin-mediated mitochondrial dysfunctions include many aspects of mitochondrial physiology such as inhibition of respiration, depletion of ubiquinone, redox imbalance, opening of the mitochondrial permeability transition pore (PTP) and disruption of energy conservation, we next outline some of these mitochondrial properties in the following sections.

During the last several decades, mitochondria have emerged as the center of attention in processes of cell signaling, cell injury, and cell death [25, 26]. According to the concept of coupling between respiration and oxidative phosphorylation through a transmembrane proton electrochemical potential that was introduced by Peter Mitchell [27], it is not difficult to understand that any condition that interferes with the ability to sustain the inner membrane proton potential leads to mitochondrial dysfunction [28]. In addition, the continuous oxygen reduction by the mitochondrial electron transport chain to build up the transmembrane proton gradient also generates a well-regulated amount of superoxide [23, 29]. Therefore, mitochondria have developed a complex antioxidant defense system composed of Mn-superoxide dismutase that converts the superoxide radical generated during respiration into hydrogen peroxide (H<sup>2</sup> O2 ). H<sup>2</sup> O2 is then reduced to water by glutathione and thioredoxin peroxidase or catalase [30]. Oxidized glutathione (GSSG) and thioredoxin (TSST) generated by peroxidases are converted to their reduced forms by glutathione and thioredoxin reductases, using NADPH as reducing power. NADH then reduces NADP<sup>+</sup> , in a reaction catalyzed by NADP transhydrogenase that is present in the inner mitochondrial membrane [31–33]. Therefore mitochondria redox state is tightly regulated and connected with whole cell redox balance [34–36]. Furthermore, it is now generally accepted that superoxide as well as other forms of ROS can function as a signal for either adaptation or maladaptation to stress conditions [35]. In this regard, mitochondrial ROS generation leads to a nonlinear dose-response relationship called mitohormesis. In mitohormesis, high reactive oxygen concentrations exert devastating and irreversible effects on cell function and structures, whereas low concentrations may be associated with protective effects due to activation of cellular defense mechanisms [37, 38]. In fact, at progressively increasing physiological levels, ROS may successively regulate cellular processes such as proliferation and differentiation, activate adaptive programs such as transcriptional upregulation of antioxidant genes, and at higher levels, ROS may be a signal for senescence and regulated cell death [35]. In addition to the physiological processes, it seems that mitochondrial oxidative stress is responsible for the development and progression of a series of diseases such as cancer, diabetes, inflammatory diseases, hypertension, neurodegenerative and ischemia-related diseases, and aging [39–46]. Statin toxicity may also include the participation of mitochondrial generated ROS [47–49].
