Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease ...and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.
Mitochondrial dysfunction is an underlying cause of ischemia-reperfusion injury. In particular, ischemic injury induces dramatic increases in mitochondrial permeability, thereby instigating a chain ...of events that leads to both apoptotic and necrotic cardiomyocyte death. The mitochondrial permeability transition (MPT) pore, a large, non-specific channel that spans the inner mitochondrial membrane, is known to mediate the lethal permeability changes that initiate mitochondrial-driven cardiomyocyte death. The purpose of this review is to focus on the role of the MPT pore in ischemia-reperfusion injury, the mechanisms involved, and, in particular, what we do and do not know regarding the pore’s molecular composition.
The emergence of mitochondria as critical regulators of cardiac myocyte survival and death has revolutionized the field of cardiac biology. Indeed, it is now well recognized that mitochondrial ...dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. A panoply of mitochondrial proteins/complexes ranging from canonical apoptosis proteins such as Bcl2 and Bax, through the mitochondrial permeability transition pore, to ion channels such as mitochondrial K(ATP) channels and connexin-43 have now been implicated as critical regulators of cardiac cell death. The purpose of this review, therefore, is to focus on these mitochondrial mediators/inhibitors of cell death and to address the specific mechanisms that underlie their ability to influence cardiac pathology.
The mitochondrion relies on compartmentalization of certain enzymes, ions and metabolites for the sake of efficient metabolism. In order to fulfil its activities, a myriad of carriers are properly ...expressed, targeted and folded in the inner mitochondrial membrane. Among these carriers, the six-transmembrane-helix mitochondrial SLC25 (solute carrier family 25) proteins facilitate transport of solutes with disparate chemical identities across the inner mitochondrial membrane. Although their proper function replenishes building blocks needed for metabolic reactions, dysfunctional SLC25 proteins are involved in pathological states. It is the purpose of the present review to cover the current knowledge on the role of SLC25 transporters in health and disease.
Abstract Uncontrolled cell death is a fundamental cause of organ disease in humans. However, despite the need for us to delineate the molecular machinery that underlies cardiomyocyte death, our ...knowledge of these lethal cellular processes is still limited. The discovery that mitochondrial dysfunction, and in particular the mitochondrial permeability transition (MPT) pore, is often a common cause of the cardiac cell mortality that underlies numerous cardiac diseases has been a first crucial step. The purpose of this review is to outline our current understanding of the molecular identity of the MPT pore and the many questions that still need to be answered.
Display omitted
•The mitochondrial permeability transition compromises cellular homeostasis.•Candidates thought to form the channel unit of the mitochondrial permeability transition pore have not ...passed loss-of-function genetic tests.•Alternative working models on the channel forming unit(s) of the mitochondrial permeability transition pore still await validation.•Future studies should follow standard guidelines to identify the channel-forming unit(s) of the mitochondrial permeability transition pore.
Mitochondria from different organisms can undergo a sudden process of inner membrane unselective leakiness to molecules known as the mitochondrial permeability transition (MPT). This process has been studied for nearly four decades and several proteins have been claimed to constitute, or at least regulate the usually inactive pore responsible for this transition. However, no protein candidate proposed as the actual pore-forming unit has passed rigorous gain- or loss-of-function genetic tests. Here we review evidence for -and against- putative channel-forming components of the MPT pore. We conclude that the structure of the MPT pore still remains largely undefined and suggest that future studies should follow established technical considerations to unambiguously consolidate the channel forming constituent(s) of the MPT pore.
Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dysfunction during diverse pathological situations. Although this bioenergetic entity has been studied ...extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease.
This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore.
While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post-translational modifications of this isomerase and its catalytic activity facilitates pore opening.
Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
As the voltage-dependent anion channel (VDAC) forms the interface between mitochondria and the cytosol, its importance in metabolism is well understood. However, research on VDAC's role in cell death ...is a rapidly growing field, unfortunately with much confusing and contradictory results. The fact that VDAC plays a role in outer mitochondrial membrane permeabilization is undeniable, however, the mechanisms behind this remain very poorly understood. In this review, we will summarize the studies that show evidence of VDAC playing a role in cell death. To begin, we will discuss the evidence for and against VDAC's involvement in mitochondrial permeability transition (MPT) and attempt to clarify that VDAC is not an essential component of the MPT pore (MPTP). Next, we will evaluate the remaining literature on VDAC in cell death which can be divided into three models: proapoptotic agents escaping through VDAC, VDAC homo- or hetero-oligomerization, or VDAC closure resulting in outer mitochondrial membrane permeabilization through an unknown pathway. We will then discuss the growing list of modulators of VDAC activity that have been associated with induction/protection against cell death. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.
► Review the evidence both for and against a role for VDACs in mitochondrial permeability transition. ► Review the literature regarding the role of VDACs in mitochondrial-dependent apoptosis. ► Discuss the factors that regulate VDAC permeability and how they influence cell death.
Guidelines for evaluating myocardial cell death Mishra, Paras K; Adameova, Adriana; Hill, Joseph A ...
American journal of physiology. Heart and circulatory physiology,
11/2019, Letnik:
317, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Cell death is a fundamental process in cardiac pathologies. Recent studies have revealed multiple forms of cell death, and several of them have been demonstrated to underlie adverse cardiac ...remodeling and heart failure. With the expansion in the area of myocardial cell death and increasing concerns over rigor and reproducibility, it is important and timely to set a guideline for the best practices of evaluating myocardial cell death. There are six major forms of regulated cell death observed in cardiac pathologies, namely apoptosis, necroptosis, mitochondrial-mediated necrosis, pyroptosis, ferroptosis, and autophagic cell death. In this article, we describe the best methods to identify, measure, and evaluate these modes of myocardial cell death. In addition, we discuss the limitations of currently practiced myocardial cell death mechanisms.
Mitochondrial supercomplexes (SCs) are the large supramolecular assembly of individual electron transport chain (ETC) complexes that apparently provide highly efficient ATP synthesis and reduce ...electron leakage and reactive oxygen species (ROS) production. Oxidative stress during cardiac ischemia-reperfusion (IR) can result in degradation of SCs through oxidation of cardiolipin (CL). Also, IR induces calcium overload and enhances reactive oxygen species (mitROS) in mitochondria that result in the opening of the nonselective permeability transition pores (PTP). The opening of the PTP further compromises cellular energetics and increases mitROS ultimately leading to cell death. Here, we examined the role of PTP-induced mitROS in disintegration of SCs during cardiac IR. The relationship between mitochondrial PTP, ROS, and SCs was investigated using Langendorff-perfused rat hearts subjected to global ischemia (25 min) followed by short-time (5 min) or long-time (60 min) reperfusion in the presence or absence of the PTP inhibitor, sanglifehrin A (SfA), and the mitochondrial targeted ROS and electron scavenger, XJB-5-131. Also, the effects of CL deficiency on SC degradation, PTP, and mitROS were investigated in tafazzin knockdown (TazKD) mice.
Cardiac IR induced PTP opening and mitROS generation, inhibited by SfA. Percent distributions of SCs were significantly affected by IR, and the effects were dependent on the reperfusion time and reversed by SfA and XJB-5-131. TazKD mice demonstrated a 40% lower SC I + III+IV with reduced basal mitochondrial PTP, ROS, and ETC complex activity. Innovation and Conclusion: Sustained reperfusion after cardiac ischemia induces disintegration of mitochondrial SCs, and PTP-induced ROS presumably play a causal role in SC disassembly. Antioxid. Redox Signal. 27, 57-69.
PDF
