Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction.

Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30-40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart.

From Physiological Redox Signalling to Oxidant Stress.

Oxidant stress is strongly associated with cardiovascular disease, including pulmonary hypertension, but antioxidant therapies have so far proven ineffective. This is partly due to a lack of understanding of the key role played by reactive oxygen species (ROS) in physiological cell signalling, and partly to the complex interrelationships between generators of ROS (e.g. mitochondria and NADPH oxidases, NOX), cellular antioxidant systems and indeed Ca2+ signalling. At physiological levels ROS reversibly affect the function of numerous enzymes and transcription factors, most often via oxidation of specific protein thiols. Importantly, they also affect pathways that promote ROS generation by NOX or mitochondria (ROS-induced ROS release), which has an inherent propensity for positive feedback and uncontrolled oxidant production. The reason this does not occur under normal conditions reflects in part a high level of compartmentalisation of ROS signalling within the cell, akin to that for Ca2+. This article considers the physiological processes which regulate NOX and mitochondrial ROS production and degradation and their interactions with each other and Ca2+ signalling pathways, and discusses how loss of spatiotemporal constraints and activation of positive feedback pathways may impact on their dysregulation in pulmonary hypertension.

Modeling the reactive oxygen species (ROS) wave in Chlamydomonas reinhardtii colonies.

Reactive oxygen species (ROS) play a crucial role as signaling molecules in both plant and animal cells, enabling rapid responses to various stimuli. Among the many cellular mechanisms used to generate and transduce ROS signals, ROS-induced-ROS release (RIRR) is emerging as an important pathway involved in the responses of various multicellular and unicellular organisms to environmental stresses. In RIRR, one cellular compartment, organelle, or cell generates or releases ROS, triggering an increased ROS production and release by another compartment, organelle, or cell, thereby giving rise to a fast propagating ROS wave. This RIRR-based signal relay has been demonstrated to facilitate mitochondria-to-mitochondria communication in animal cells and long-distance systemic signaling in plants in response to biotic and abiotic stresses. More recently, it has been discovered that different unicellular microorganism communities also exhibit a RIRR cell-to-cell signaling process triggered by a localized stress treatment. However, the precise mechanism underlying the propagation of the ROS signal among cells within these unicellular communities remained elusive. In this study, we employed a reaction-diffusion model incorporating the RIRR mechanism to analyze the propagation of ROS-mediated signals. By effectively balancing production and scavenging processes, our model successfully reproduces the experimental ROS signal velocities observed in unicellular green algae (Chlamydomonas reinhardtii) colonies grown on agar plates, furthering our understanding of intercellular ROS communication.

Pharmacological strategies to lower crosstalk between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria.

Reactive oxygen species (ROS) are the metabolites of oxygen that plays a significant role in cell signaling and homeostasis. Under normal conditions, ROS formation is stabilized by various antioxidant defense systems (ROS scavengers). Several studies in both in-vitro and in-vivo models, together with clinical data indicated that increased production ROS and oxidative stress plays a crucial role in the development and progression of endothelial dysfunction. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain unclear. The purpose of this review is to outline various sources of ROS and describe the crosstalk between NADPH oxidase and mitochondria. Further, we will discuss different antioxidants that lower ROS production and ROS-induced pathological conditions such as aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders. In this review, we have mainly focused on antioxidants that inhibit NADPH oxidase and mitochondrial sources of ROS. Moreover, the modification of antioxidants (targeted therapy) may be a significant approach for management of oxidative stress induced pathophysiological complications.

ROS-induced ROS release in plant and animal cells.

Reactive oxygen species (ROS) play a key signaling role in plant and animal cells. Among the many cellular mechanisms used to generate and transduce ROS signals, ROS-induced ROS release (RIRR) is emerging as an important pathway involved in different human pathologies and plant responses to environmental stress. RIRR is a process in which one cellular compartment or organelle generates or releases ROS, triggering the enhanced production or release of ROS by another compartment or organelle. It was initially described in animal cells and proposed to mediate mitochondria-to-mitochondria communication, but later expanded to include communication between mitochondria and plasma membrane-localized NADPH oxidases. In plants a process of RIRR was demonstrated to mediate long distance rapid systemic signaling in response to biotic and abiotic stress. This process is thought to involve the enhanced production of ROS by one cell that triggers the enhanced production of ROS by a neighboring cell in a process that propagates the enhanced "ROS production state" all the way from one part of the plant to another. In contrast to the intracellular nature of the RIRR process of animal cells, the plant RIRR process is therefore primarily studied at the cell-to-cell communication level. Studies on intracellular (organelle-to-organelle, or organelle-to-NADPH oxidase) RIRR pathways are very scarce in plants, whereas studies on cell-to-cell RIRR are very scarce in animals. Here we will attempt to highlight what is known in both systems and what each system can learn from the other.

Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes.

AIMS: Studies in guinea-pig cardiomyocytes show that reactive oxygen species (ROS) produced by a few mitochondria can propagate to their neighbours, triggering synchronized, cell-wide network oscillations via an ROS-induced ROS release (RIRR) mechanism. How mitochondria in cardiomyocytes from failing hearts (HF) respond to local oxidative stress perturbations has not been investigated. Since mitochondrial ultrastructure is reportedly disrupted in HF, and propagation of ROS signals depends on mitochondrial network integrity, we hypothesized that the laser flash-induced RIRR is altered in HF. METHODS AND RESULTS: To test the hypothesis, pressure-overload HF was induced in guinea pigs by ascending aortic constriction leading to left ventricular dilatation and decreased ejection fraction after 8 weeks. Isolated cardiomyocytes were studied with two-photon/confocal microscopy to determine their basal oxidative stress and propensity to undergo mitochondrial depolarization/oscillations in response to local laser flash stimulations. The expression of mitofusin proteins and mitochondrial network structure were also analysed. Results showed that HF cardiomyocytes had higher baseline ROS levels and less reduced glutathione, and were more prone to laser flash-induced mitochondrial depolarization. In contrast, the delay between the laser flash and synchronized cell-wide network oscillations was prolonged in HF myocytes compared with shams, and the spatial extent of coupling was diminished, suggesting dampened RIRR and ROS signal propagation. In addition, the expressions of mitofusin proteins in HF myocardium were down-regulated compared with these from sham-operated animals, and the mitochondrial network structure altered. CONCLUSION: The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF.