Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. Export

@article{citeulike:1030144, abstract = {To obtain further information on time course and mechanisms of cell death after poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, we used HeLa cells exposed for 1 h to the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. This treatment activated PARP-1 and caused a rapid drop of cellular NAD(H) and ATP contents, culminating 8-12 h later in cell death. PARP-1 antagonists fully prevented nucleotide depletion and death. Interestingly, in the early 60 min after challenge with N-methyl-N'-nitro-N-nitrosoguanidine, mitochondrial membrane potential and superoxide production significantly increased, whereas cellular ADP contents decreased. Again, these events were prevented by PARP-1 inhibitors, suggesting that PARP-1 hyperactivity leads to mitochondrial state 4 respiration. Mitochondrial membrane potential collapsed at later time points (3 h), when mitochondria released apoptosis-inducing factor and cytochrome c. Using immunocytochemistry and targeted luciferase transfection, we found that, despite an exclusive localization of PARP-1 and poly(ADP-ribose) in the nucleus, ATP levels first decreased in mitochondria and then in the cytoplasm of cells undergoing PARP-1 activation. PARP-1 inhibitors rescued ATP (but not NAD(H) levels) in cells undergoing hyper-poly(ADP-ribosyl)ation. Glycolysis played a central role in the energy recovery, whereas mitochondria consumed ATP in the early recovery phase and produced ATP in the late phase after PARP-1 inhibition, further indicating that nuclear poly(ADP-ribosyl)ation rapidly modulates mitochondrial functioning. Together, our data provide evidence for rapid nucleus-mitochondria cross-talk during hyper-poly(ADP-ribosyl)ation-dependent cell death.}, address = {Department of Pharmacology, University of Florence, 50139 Florence, Italy.}, author = {Cipriani, G. and Rapizzi, E. and Vannacci, A. and Rizzuto, R. and Moroni, F. and Chiarugi, A.}, citeulike-article-id = {1030144}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M414526200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15750180}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15750180}, day = {29}, doi = {10.1074/jbc.M414526200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {apoptosis, nadh, parp, redox-status}, month = {April}, number = {17}, pages = {17227--17234}, posted-at = {2007-01-08 13:52:26}, priority = {2}, title = {Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction.}, url = {http://dx.doi.org/10.1074/jbc.M414526200}, volume = {280}, year = {2005} }

TY - JOUR ID - citeulike:1030144 L3 - citeulike-article-id:1030144 N2 - To obtain further information on time course and mechanisms of cell death after poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, we used HeLa cells exposed for 1 h to the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. This treatment activated PARP-1 and caused a rapid drop of cellular NAD(H) and ATP contents, culminating 8-12 h later in cell death. PARP-1 antagonists fully prevented nucleotide depletion and death. Interestingly, in the early 60 min after challenge with N-methyl-N'-nitro-N-nitrosoguanidine, mitochondrial membrane potential and superoxide production significantly increased, whereas cellular ADP contents decreased. Again, these events were prevented by PARP-1 inhibitors, suggesting that PARP-1 hyperactivity leads to mitochondrial state 4 respiration. Mitochondrial membrane potential collapsed at later time points (3 h), when mitochondria released apoptosis-inducing factor and cytochrome c. Using immunocytochemistry and targeted luciferase transfection, we found that, despite an exclusive localization of PARP-1 and poly(ADP-ribose) in the nucleus, ATP levels first decreased in mitochondria and then in the cytoplasm of cells undergoing PARP-1 activation. PARP-1 inhibitors rescued ATP (but not NAD(H) levels) in cells undergoing hyper-poly(ADP-ribosyl)ation. Glycolysis played a central role in the energy recovery, whereas mitochondria consumed ATP in the early recovery phase and produced ATP in the late phase after PARP-1 inhibition, further indicating that nuclear poly(ADP-ribosyl)ation rapidly modulates mitochondrial functioning. Together, our data provide evidence for rapid nucleus-mitochondria cross-talk during hyper-poly(ADP-ribosyl)ation-dependent cell death. IS - 17 JF - J Biol Chem SN - 0021-9258 AD - Department of Pharmacology, University of Florence, 50139 Florence, Italy. EP - 17234 TI - Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. VL - 280 SP - 17227 KW - apoptosis KW - nadh KW - parp KW - redox-status AU - Cipriani, G AU - Rapizzi, E AU - Vannacci, A AU - Rizzuto, R AU - Moroni, F AU - Chiarugi, A PY - 2005/04/29/ UR - http://dx.doi.org/10.1074/jbc.M414526200 ER -