Serial Review: The powerhouse takes control of the cell; the role of mitochondria in signal transductionMitochondrial dysfunction in cardiovascular disease☆
Introduction
With exception of the worldwide Spanish influenza epidemic of 1918, cardiovascular disease (CVD) has been the leading cause of mortality and morbidity in the United States every year since 1900 [1]. Atherosclerosis is the leading cause of CVD-related mortality, accounting for nearly three-fourths of all deaths from heart disease. Endothelial cell injury and inflammation are thought to be the first steps in the development of atherosclerosis, which can lead to the accumulation of lipids in injured areas of the artery. Increased adherence of monocytes/macrophages leads to the formation of lipid-engorged “foam cells,” which together with T lymphocytes, become “fatty streaks,” Fatty streaks can progress (via continued cell influx and proliferation) to an intermediate, atherosclerotic fibro-fatty lesion and ultimately to a fibrous plaque. Eventually, arterial wall thickening, plaque rupture, and occlusion lead to the clinical manifestations of CVD, myocardial ischemia, and infarction (heart attack) [2], [3], [4], [5], [6], [7]. Although CVD is typically considered to be an “adult” disease, the events that lead to atherosclerosis probably begin decades before the clinical manifestations of the disease become evident. Hence, atherosclerosis can be a slow, complex inflammatory disease that can start in childhood and progress with age. Although much is known about the progression and development of CVD, its specific underlying etiology remains elusive.
A plethora of studies have revealed that among the potential causes of CVD, free radical-mediated changes within the cardiovascular milieu are currently the most popular suspects [8], [9], [10], [11], [12]. The concept that oxidative stress is important in the pathogenesis of CVD was conceived from studies that noted the cytotoxic and atherogenic properties of oxidized LDL (oxLDL) cholesterol [13], [14], [15], [16], [17]. Subsequently, it has become apparent that native LDL cholesterol can be converted to oxLDL cholesterol via several pathways involving oxidative and/or nitrosoxidative stress [10]. An enormous amount of study and discovery has been made regarding the multiple potential sources of cellular oxidative and/or nitrosoxidative stress (e.g., NADPH oxidase, xanthine oxidase, myeloperoxidase, mitochondria, and iNOS) [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31] (Fig. 1).
Whereas it is clear that proteins, membranes, lipids, and genetic materials are susceptible to damage mediated by oxidative and nitrosoxidative stress, it is not yet clear whether a “common” subcellular target exists which is vulnerable to free radical-mediated damage that will be relevant to CVD development. Subcellular components that play important roles in a variety of cell functions, including growth, death, signaling, and bioenergetics would appear to be important candidates in this regard.
Section snippets
Mitochondrial oxidative phosphorylation and mitochondrial DNA
Numerous reports have shown that mitochondria are sensitive to both reactive oxygen- and nitrogen species-mediated damage and alterations in function [25], [32], [33], [34], [35], [36], [37]. Because they are the major source of oxidative energy for the cell, mitochondria have been stereotyped as “cellular powerplants.” Mitochondrial oxidative phosphorylation (OXPHOS) consists of five multiple subunit enzyme complexes embedded within the mitochondrial inner membrane, which coordinately function
Mitochondrial DNA mutations and human disease
MtDNA mutations have been associated with a wide array of human diseases and can show marked clinical heterogeneity, including deficits in neuromuscular, musculoskeletal, cardiovascular, renal, endocrine, and neural function. Cardiac complications, particularly cardiac dysrhythmias and cardiomyopathy, are prominent features of many diseases associated with mtDNA mutations. Much of the clinical variability of diseases caused by specific mtDNA mutations appears to result from: (i) the severity of
Mitochondrial-derived oxidants
More recently, it has been noted that the mitochondrion also serves as a primary cellular source of endogenous oxidants. Whereas the majority of oxygen consumed by the mitochondrion is converted to water at complex IV (cytochrome c oxidase), oxygen can pick up electrons directly from the ubiquinone site in complex III and flavin mononucleotide group of complex I to generate O2− [25], [58]. Recently, it has been shown that electrons derived from FADH2 (complex II substrate) can undergo “reverse
Regulation of mitochondrial oxidant production
A number of physiologic factors regulate mitochondrial oxidant generation, including local concentrations of both reactive nitrogen and oxygen species, mitochondrial antioxidants, electron transport efficiency, metabolic reducing equivalent availability (NADH and FADH2), uncoupling protein (UCP) activities, cytokines, and overall organelle integrity (damage to membranes, DNA, and proteins). Low NO concentrations can modulate mitochondrial respiration and oxygen consumption through reversible
Mitochondria are targets of ROS
Whereas ROS and RNS are capable of targeting a variety of subcellular components, the mitochondrial membranes, proteins, and mtDNA appear particularly sensitive to oxidative and nitrosative damage [33], [34], [37], [95], [96], [97]. Studies have shown that reactive species such as H2O2 and ONOO− can induce a variety of effects, including preferential and sustained mtDNA damage, altered mitochondrial transcript levels and mitochondrial protein synthesis, and lowered mitochondrial redox
Mitochondrial damage/dysfunction is associated with CVD
Several lines of evidence suggest that an association exists among CVD development, mitochondrial damage, and function. It has been shown that CVD patients have increased mtDNA damage when compared with healthy controls in both the heart and the aorta [51], [53], [102], [111]. Atherosclerotic lesions in brain microvessels from Alzheimer's (AD) patients and rodent AD models have significantly more mtDNA deletions and abnormalities (as do the endothelium and perivascular cells), suggesting that
Conclusions
By virtue of their ability to modulate local subcellular oxidant levels through a complex interaction of respiratory regulation, coupling, antioxidant activity, and relative balance of ROS and RNS, mitochondria can play critical functions in cell signaling, growth, and death. Consequently, in some cell types, mitochondrial modulation of redox regulation (e.g., in response to NO and/or cytokines) may be the initial defect, not energy production. Hence, although it was originally thought that
Acknowledgments
This work was supported by NIH Grants ES 11172 and HL 77419.
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This article is part of a series of reviews on “The Powerhouse Takes Control of the Cell: the Role of Mitochondria in Signal Transduction.” The full list of papers may be found on the home page of the journal.