review · Molecular Biology Reports
Ischemia-reperfusion injury significantly undermines outcomes following organ transplantation. Oxygen deprivation during ischemia disrupts cellular metabolism and lowers bioenergetics through mitochondrial electron transport chain dysfunction, forcing a shift to anaerobic metabolism. This shift triggers an influx of intracellular sodium, hydrogen, and calcium ions, leading to cellular oedema. When blood flow is subsequently restored, the surplus of oxygen drives excessive production of reactive oxygen species, overwhelming endogenous antioxidant defences and initiating oxidative and inflammatory damage. Although cells can activate survival systems to recover from moderate injury, severe or prolonged ischemia and reperfusion induce widespread cell death through multiple pathways, including apoptosis, necrosis, ferroptosis, and pyroptosis. Inhibiting these specific death cascades offers clinical potential for improving allograft quality and preservation.
Organ transplants often suffer severe tissue damage when blood supply is interrupted and then restored. Understanding the exact molecular chains of events that lead to cell death allows researchers to identify targeted ways to protect donor organs. Successfully preventing this damage could directly improve organ viability, reduce post-transplant complications, and prolong the functional lifespan of transplanted tissues.
The findings outline targets for preventing organ damage, which could inform the development of novel organ preservation solutions, perfusion machine additives, or therapeutic inhibitors by biotechnology and pharmaceutical companies. As a review of cellular and molecular mechanisms, the work is at an early research stage, pointing toward target identification and preclinical testing rather than near-market interventions.
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Ischemia-reperfusion injury (IRI) is a critical pathological condition in which cell death plays a major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs cellular metabolism and decreases cellular bioenergetics through dysfunction of mitochondrial electron transport chain, causing a switch from cellular respiration to anaerobic metabolism, and subsequent cascades of events that lead to increased intracellular concentrations of Na<sup>+</sup>, H<sup>+</sup> and Ca<sup>2+</sup> and consequently cellular edema. Restoration of blood supply after ischemia provides oxygen to the ischemic tissue in excess of its requirement, resulting in over-production of reactive oxygen species (ROS), which overwhelms the cells' antioxidant defence system, and thereby causing oxidative damage in addition to activating pro-inflammatory pathways to cause cell death. Moderate ischemia and reperfusion may result in cell dysfunction, which may not lead to cell death due to activation of recovery systems to control ROS production and to ensure cell survival. However, prolonged and severe ischemia and reperfusion induce cell death by apoptosis, mitoptosis, necrosis, necroptosis, autophagy, mitophagy, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, pyroptosis, cuproptosis and parthanoptosis. This review discusses cellular and molecular mechanisms of these various forms of cell death in the context of organ transplantation, and their inhibition, which holds clinical promise in the quest to prevent IRI and improve allograft quality and function for a long-term success of organ transplantation.
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DOI: 10.1007/s11033-024-09261-7
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