Lemasters 1998 Biochim Biophys Acta

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Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177-96.

» PMID: 9714796

Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B (1998) Biochim Biophys Acta

Abstract: Using confocal microscopy, onset of the mitochondrial permeability transition (mtPT) in individual mitochondria within living cells can be visualized by the redistribution of the cytosolic fluorophore, calcein, into mitochondria. Simultaneously, mitochondria release membrane potential-indicating fluorophores like tetramethylrhodamine methylester. The mtPT occurs in several forms of necrotic cell death, including oxidative stress, pH-dependent ischemia/reperfusion injury and Ca2+ ionophore toxicity. Cyclosporin A (CsA) and trifluoperazine block the mtPT in these models and prevent cell killing, showing that the mtPT is a causative factor in necrotic cell death. During oxidative injury induced by t-butylhydroperoxide, onset of the mtPT is preceded by pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and an increase of mitochondrial free Ca2+, all changes that promote the mtPT. During tissue ischemia, acidosis develops. Because of acidotic pH, anoxic cell death is substantially delayed. However, when pH is restored to normal after reperfusion (reoxygenation at pH 7.4), cell death occurs rapidly (pH paradox). This killing is caused by pH-dependent onset of the mtPT, which is blocked by reperfusion at acidotic pH or with CsA. In isolated mitochondria, toxicants causing Reye's syndrome, such as salicylate and valproate, induce the mtPT. Similarly, salicylate induces a CsA-sensitive mtPT and killing of cultured hepatocytes. These in vitro findings suggest that the mtPT is the pathophysiological mechanism underlying Reye's syndrome in vivo. Kroemer and coworkers proposed that the mtPT is a critical event in the progression of apoptotic cell death. Using confocal microscopy, the mtPT can be directly documented during tumor necrosis factor-alpha induced apoptosis in hepatocytes. CsA blocks this mtPT and prevents apoptosis. The mtPT does not occur uniformly during apoptosis. Initially, a small proportion of mitochondria undergo the mtPT, which increases to nearly 100% over 1-3 h. A technique based on fluorescence resonance energy transfer can selectively reveal mitochondrial depolarization. After nutrient deprivation, a small fraction of mitochondria spontaneously depolarize and enter an acidic lysosomal compartment, suggesting that the mtPT precedes the normal process of mitochondrial autophagy. A model is proposed in which onset of the mtPT to increasing numbers of mitochondria within a cell leads progressively to autophagy, apoptosis and necrotic cell death.

Bioblast editor: Gnaiger E


Stress:Cell death, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS 

Tissue;cell: Liver  Preparation: Intact cells, Isolated mitochondria 

Regulation: Calcium, mt-Membrane potential, pH