Pharmacologic and Metabolic Mitochondrial Rescue

Abstract

Studies dating back four decades have implicated mitochondrial damage in the pathogenesis of cell injury during ischemia/reperfusion and hypoxia/reoxygenation. Multiple structural and biochemical changes have been described [1, 2]. These include development of condensation or swelling of the mitochondrial matrix depending on the stage of the lesion [3], impairment of electron transport most consistently involving complex I of the electron transport chain, but not limited to it [4, 5], functional abnormalities of other inner membrane proteins such as the adenine nucleotide translocase and the F₁F₀-ATPase [5–8], and increases of inner membrane permeability [9–11]. However, the pathogenic significance of most of these changes and, indeed, the question of whether mitochondrial dysfunction plays a decisive role in cell injury remained subject to debate and uncertainty [1, 2, 5] because of a number of confounding factors. The mitochondrial inner membrane permeability alterations appeared to be nonspecific. Effects of massive post lethal cellular calcium influx confounded interpretation of more pathogenically relevant earlier events in many studies. The specific defect responsible for lethal plasma membrane damage during ATP depletion conditions that produce rapid, necrotic cell death was not defined. The importance of apoptotic cell death was not appreciated and its mechanisms were unknown. The vast majority of measurements used isolated mitochondria, which are subject to selection and further damage during their preparation and which, under typical in vitro study conditions, lack extra-mitochondrial protective mechanisms that modulate injury as it occurs within cells. In some instances, ATP depletion per se appeared to be insufficient to account for the cellular damage associated with mitochondrial dysfunction, and, in others [1], overall cellular injury was paradoxically promoted by energetic recovery.