No abstract

Bioenergetic dysfunction is emerging as a cornerstone for establishing a framework for understanding the pathophysiology of cardiovascular disease, diabetes, cancer and neurodegeneration. Recent advances in cellular bioenergetics have shown that many cells maintain a substantial bioenergetic reserve capacity, which is a prospective index of “healthy” mitochondrial populations. The bioenergetics of the cell are likely regulated by energy requirements and substrate availability. Additionally, the overall quality of the mitochondrial population and the relative abundance of mitochondria in cells and tissues also impinge on overall bioenergetic capacity and resistance to stress. Because mitochondria are susceptible to damage mediated by reactive oxygen/nitrogen and lipid species, maintaining a “healthy” population of mitochondria through quality control mechanisms appears to be essential for cell survival under conditions of pathological stress. Accumulating evidence suggest that mitophagy is particularly important for preventing amplification of initial oxidative insults, which otherwise would further impair the respiratory chain or promote mutations in mitochondrial DNA (mtDNA). The processes underlying the regulation of mitophagy depend on several factors including the integrity of mtDNA, electron transport chain activity, and the interaction and regulation of the autophagic machinery. The integration and interpretation of cellular bioenergetics in the context of mitochondrial quality control and genetics is the theme of this review.

Bioenergetics has become central to our understanding of pathological mechanisms, the development of new therapeutic strategies and as a biomarker for disease progression in neurodegeneration, diabetes, cancer and cardiovascular disease. A key concept is that the mitochondrion can act as the ‘canary in the coal mine’ by serving as an early warning of bioenergetic crisis in patient populations. We propose that new clinical tests to monitor changes in bioenergetics in patient populations are needed to take advantage of the early and sensitive ability of bioenergetics to determine severity and progression in complex and multifactorial diseases. With the recent development of high-throughput assays to measure cellular energetic function in the small number of cells that can be isolated from human blood these clinical tests are now feasible. We have shown that the sequential addition of well-characterized inhibitors of oxidative phosphorylation allows a bioenergetic profile to be measured in cells isolated from normal or pathological samples. From these data we propose that a single value–the Bioenergetic Health Index (BHI)–can be calculated to represent the patient's composite mitochondrial profile for a selected cell type. In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes. We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

Background-Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS. Methods and Results-We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E Ϫ/Ϫ mice but also preceded atherogenesis in young apolipoprotein E Ϫ/Ϫ mice. Apolipoprotein E Ϫ/Ϫ mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a phenotype of accelerated atherogenesis at arterial branch points. Key Words: atherosclerosis Ⅲ muscle, smooth Ⅲ antioxidants R eactive species (RS) define a collective grouping of reactive oxygen and nitrogen species that can alter the biological functions of essential molecules such as lipids, proteins, and DNA. Numerous studies have linked excess RS generation with vascular lesion formation and functional defects. [1][2][3] This association has been reported for various RS models and species. 4 -6 A role for RS in atherogenesis is supported by epidemiological evidence of links between common risk factors for coronary artery disease and increased levels of RS. [7][8][9] Among the extensively studied intracellular systems capable of generating RS in vascular cells are the NADH/NADPH oxidase, xanthine oxidase, lipoxygenase, and cyclooxygenase systems. 6,10 -12 Mitochondria are biologically important sources and targets for RS. 13,14 However, their role as mediators of oxidative disease processes such as atherogenesis has not been examined. We recently reported that exposure of vascular cells to RS in vitro results in preferential mitochondrial DNA (mtDNA) damage and dysfunction and that mtDNA damage is a very sensitive marker for RS-mediated cellular effects. 15 In addition to the potential role of mtDNA damage as a marker of ambient oxidative stress, oxidative damage to the mitochondrion can lead to decreased oxidative energetic capacity (via impaired oxidative phosphorylation) and increased generation of intracellular RS. 15-17 Thus, we hypothesized that mitochondrial dysfunction accentuates atherosclerosis by modulating the phenotype of vascular cells and that measurements of mtDNA damage reflect RS-mediated atherosclerosis risk. Conclusions-MitochondrialUsing human aortic specimens and a murine model of early atherogenesis (the apolipoprotein E null, apoE Ϫ/Ϫ ), we examined the correlation between mtDNA damage and atherogenesis and sought to determine whether mtDNA damage is a cause or an effect in this pr...