Cellular and molecular mechanisms of cell damage and cell death in ischemia-reperfusion injury in organ transplantation

Abstract

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⁺, H⁺ and Ca²⁺ 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.

Keywords: Apoptosis; Autophagy; Ferroptosis; Ischemia–reperfusion injury (IRI); Necroptosis; Necrosis; Organ transplantation; Parthanoptosis; Pyroptosis.

Fig. 1

Summary of cellular events during ischemia: 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 a cascade of events that leads to increased intracellular concentrations of Na⁺, H⁺ and Ca²⁺ and consequently cellular edema

Fig. 2

Summary of the pathway leading to cell damage and cell death during reperfusion. Restoration of blood supply to ischemic tissue 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 stress and lipid peroxidation in the cell membranes in addition to activating pro-inflammatory pathways to cause cell death