Mitochondria are critical players in cell injury and cell death by all pathways. This should be expected because they supply life-sustaining energy by producing ATP. Mitochondria can be damaged by increases of cytosolic Ca2+, reactive oxygen species (discussed later), and oxygen deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins. In addition, mutations in mitochondrial genes are the cause of some inherited diseases.
There are three major consequences of mitochondrial damage.
• Mitochondrial damage often results in the formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore (Fig. 1). The opening of this conductance channel leads to the loss of mitochondrial membrane potential, resulting in failure of oxidative phosphorylation and progressive depletion of ATP, culminating in necrosis of the cell. One of the structural components of the mitochondrial permeability transition pore is the protein cyclophilin D, which is one of several cyclophilins that are targeted by the immunosuppressive drug cyclosporine (used to prevent graft rejection). In some experimental models of ischemia, cyclosporine reduces injury by preventing opening of the mitochondrial permeability transition pore—an interesting example of molecularly targeted therapy for cell injury. The role of cyclosporine in reducing ischemic myocardial injury in humans is under investigation.
• Abnormal oxidative phosphorylation also leads to the formation of reactive oxygen species, which have many deleterious effects, described later.
• The mitochondria sequester between their outer and inner membranes several proteins that are capable of activating apoptotic pathways; these include cytochrome c and proteins that indirectly activate apoptosisinducing enzymes called caspases. Increased permeability of the outer mitochondrial membrane may result in leakage of these proteins into the cytosol and death by apoptosis (discussed later).
Fig1. Role of mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis. ATP, Adenosine triphosphate; ROS, reactive oxygen species.
