02 May 2003
Med Sci Monit 2003; 9(1): 66- :: ID: 15205
Mitochondrial permeability transition (MPT) leads to cell death in ischemia and inflammation . Here we show that PARP-1 causes cell death through a process involving NAD+ depletion and mitochondrial permeability transition. PARP-1 activation in cultured mouse neurons or astrocytes led to delayed mitochondrial membrane depolarization and to MPT. These changes were prevented in PARP-1 deficient cells, with PARP inhibitors, or with sub-micromolar concentrations of MPT inhibitors, but not by the calcineurin inhibitor FK506. PARP-1-induced cell death was similarly blocked by MPT inhibitors but not FK506. Translocation of AIF from mitochondria to the nucleus, which has previously been linked PARP-1-induced cell death , did not occur when MPT was prevented. Last, repletion of intracellular NAD+ concentrations in PARP-1 activated cells prevented MPT, AIF translocation, and cell death. These results suggest that the NAD+ depletion is an upstream event in the PARP-1 cell death pathway, with NAD+ depletion leading to MPT, and MPT in turn leading to AIF translocation and cell death. References: 1.Halestrap AP: The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury. Biochem Soc Symp, 1999; 66: 181-203 2.Yu SW, Wang H, Poitras MF et al: Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science, 2002; 297: 259-263
Keywords: AIF, nicotinamide adenine dinucleotide, cyclosporin, membrane potential
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