Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death

Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptotic cell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening of a high conductance permeability tr ansition (PT) pore in the mitochondrial inner membrane abruptly increases t he permeability of the mitochondrial inner membrane to solutes of molecular mass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeabi lity transition (MPT) and prevents necrotic cell death from oxidative stres s, Ca2+ ionophore toxicity, Reye related drug toxicity, pH-dependent ischem ia/reperfusion injury, and other models of cell injury. Confocal fluorescen ce microscopy directly visualizes onset of the MPT from the movement of gre en-fluorescing calcein into mitochondria and the simultaneous release from mitochondria of red-fluorescing tetramethylrhodamine methylester, a membran e potential-indicating fluorophore. In oxidative stress to hepatocytes indu ced by tert-butylhydroperoxide, NAD(P)H oxidation, increased mitochondrial Ca2+, and mitochondrial generation of reactive oxygen species precede and c ontribute to onset of the MPT. Confocal microscopy also shows directly that the MPT is a critical event in apoptosis of hepatocytes induced by tumor n ecrosis factor-alpha. Progression to necrotic and apoptotic cell killing de pends, at least in part, on the effect the MPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATP levels are a t least partially maintained, apoptosis follows the MPT. Cellular features of both apoptosis and necrosis frequently occur together:after death signal s and toxic stresses. A new term, necrapoptosis, describes such death proce sses that begin with a common stress or death signal, progress by shared pa thways, but Culminate in either cell lysis (necrosis) or programmed cellula r resorption (apoptosis) depending on modifying factors such as ATP.