THE MITOCHONDRIAL PERMEABILITY TRANSITION IN TOXIC, HYPOXIC AND REPERFUSION INJURY

Opening of a non-specific, high conductance permeability transition po re or megachannel in the inner mitochondrial membrane causes onset of the mitochondrial permeability transition, which is characterized by m itochondrial swelling, depolarization and uncoupling. Inducers of the permeability transition include Ca2+, oxidant stress and a permissive pH greater than 7.0. Blockers include cyclosporin A, trifluoperazine a nd pH < 7. Using laser scanning confocal microscopy, we developed tech niques to visualize onset of the mitochondrial permeability transition in situ in living cells. In untreated cells, the permeability transit ion pore is continuously closed and does not 'flicker' open. By contra st, the pore opens in liver and heart cells after exposure to oxidant chemicals, calcium ionophore, hypoxia and ischemia/reperfusion, causin g mitochondrial uncoupling and aggravation of ATP depletion. In injury to hepatocytes from tert-butylhydroperoxide, an analog of lipid hydro peroxides generated during oxidative stress, onset of the mitochondria l permeability transition is preceded by oxidation of mitochondrial py ridine nucleotides, mitochondrial generation of oxygen radicals and an increase of mitochondrial Ca2+, all inducers of the mitochondrial per meability transition. In ischemia, the acidosis of anaerobic metabolis m protects strongly against cell death. During reperfusion, recovery o f pH to normal levels is a stress that actually precipitates cell kill ing. Onset of the mitochondrial permeability transition may be respons ible, in part, for this pi-I-dependent injury, or pH paradox. The mito chondrial permeability transition may also be responsible for a variet y of pathological phenomena. In particular, the mitochondrial permeabi lity transition may underlie Reye's syndrome and Reye's-like drug toxi cities. In conclusion, multiple mechanisms contribute to cell injury a fter hypoxia, ischemia/reperfusion and toxic chemicals, but a common f inal pathway leading to acute cellular necrosis may be ATP depletion a fter mitochondrial failure. One important mechanism causing mitochondr ial failure is the mitochondrial permeability transition, which both u ncouples oxidative phosphorylation and accelerates ATP hydrolysis. Int erventions that block this pH-dependent phenomenon protect against ons et of cell death.