Cardiac Mitochondria and Reactive Oxygen Species Generation

Abstract

Mitochondrial ROS have emerged as an important mechanism of disease and redox signaling in the cardiovascular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by the electron transport chain and proton motive force consisting of a membrane potential (ΔΨ) and a proton gradient (ΔpH). Several factors controlling ROS production in mitochondria include FMN and the FMN-binding domain of complex I, ubisemiquinone and quinone-binding domain of complex I, FAD binding moiety and quinone-binding pocket (Qp) of complex II, and unstable semiquinone •Qo− mediated by the Q cycle of complex III. In mitochondrial complex I, specific cysteinyl redox domains modulate ROS production from the FMN moiety and iron sulfur clusters. In the cardiovascular system, mitochondrial ROS have been linked to mediating physiological effects of metabolic dilation and preconditioning-like mKATP channel activation. Furthermore, oxidative post-translational modification by glutathione in complex I and complex II has been shown to affect enzymatic catalysis, protein-protein interactions, and enzyme-mediated ROS production. Conditions associated with oxidative or nitrosative stress, such as myocardial ischemia and reperfusion, increase mitochondrial ROS production via oxidative injury of complexes I and II, and •O2−-induced hydroxyl radical production by aconitase. Further insight into cellular mechanisms by which specific redox post-translational modifications regulate ROS production in mitochondria will enrich our understanding of redox signal transduction and identify new therapeutic targets for cardiovascular diseases in which oxidative stress perturbs normal redox signaling.

The role of mitochondria in cardiac development and protection

“…Although the one electron reduction of O2 to O2 -· is thermodynamically favored under physiological conditions, only few cellular electron carriers are able to carry out this reaction and for example, the electron transport in mitochondria is tightly coupled to the reduction of O2 to H2O under normal conditions. However, uncontrolled leakage of electrons through complexes I-III can generate superoxide, especially when the rate of ADP phosphorylation is decreased and the membrane proton gradient is high [18,19]. Besides spontaneous dismutation, superoxide can be rapidly converted to hydrogen peroxidase (H2O2) by the mitochondrial superoxide dismutase (SOD2) and further to H2O by catalase or glutathione peroxidases (GSHs).…”

“…Mechanistically this could be achieved through supercomplex organization, which has direct consequences on substrate channeling, electron transport efficiency and ROS production from CI [13,16,22]. Consequently, if the ETC is compromised, heart mitochondria become effective ROS generators due to their active OXPHOS [18]. Such a crisis can be caused e.g.…”

“…It has been suggested that the increased electron leakage from various parts of the reduced electron transport chain to the residual O2 might produce O2 -· [18], however, hypoxia seems to lower ROS production in vitro indicating that the mechanism is more complex in vivo [19].…”

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

“…Since ablation of LAMP2 prevented this preconditioning effect with accumulation of abnormal mitochondria (Figs. 2G, 3, 4G, and 6E-H), and damaged mitochondria provoke increased generation of reactive oxygen species (ROS) in the myocardium, 38 we hypothesized that intermittent fasting regulates myocardial ROS generation via effects on mitochondria, which is lost in the setting of Lamp2 ablation due to impairment in mitochondrial autophagy. Indeed, we observed a significant reduction in myocardial levels of oxidatively modified proteins in intermittently fasted wild-type mice of both sexes as compared with ad libitum fed controls (Fig.…”

Effect of Sodium Thiosulfate on Isolated Cardiac Interfibrillar and Subsarcolemmal Mitochondria

“…Incidentally, the majority of intracellular reactive oxygen species (ROS, superoxide, hydroxide and hydrogen peroxide) that mediate the oxidative stress, are derived from mitochondria via electron transport chain (ETC), especially complex I and complex III redox sites [1][2][3] . Ischemia reperfusion (I/R) injury, a major contributor to the damage encountered during myocardial infarction is experimentally studied by performing microsurgery on rodents; isolated heart perfusion with Langendorff setup and by mimicking it in cell lines utilizing anaerobic chamber.…”