Intra-mitochondrial Poly(ADP-ribosylation) Contributes to NAD+ Depletion and Cell Death Induced by Oxidative Stress
Poly(ADP-ribosylation), primarily via poly(ADP-ribose) polymerase-1 (PARP-1), is a pluripotent cellular process important for maintenance of genomic integrity and RNA transcription in cells. However, during conditions of oxidative stress and energy depletion, poly(ADP-ribosylation) paradoxically contributes to mitochondrial failure and cell death. Although it has been presumed that poly(ADP-ribosylation) within the nucleus mediates this pathologic process, PARP-1 and other poly(ADP-ribosyltransferases) are also localized within mitochondria. To this end, the presence of PARP-1 and poly(ADP-ribosylation) were verified within mitochondrial fractions from primary cortical neurons and fibroblasts. Inhibition of poly(ADP-ribosylation) within the mitochondrial compartment preserved transmembrane potential (ΔΨm), NAD+content, and cellular respiration, prevented release of apoptosis-inducing factor, and reduced neuronal cell death triggered by oxidative stress. Treatment with liposomal NAD+ also preserved ΔΨm and cellular respiration during oxidative stress. Furthermore, inhibition of poly(ADP-ribosylation) prevented intranuclear localization of apoptosis-inducing factor and protected neurons from excitotoxic injury; and PARP-1 null fibroblasts were protected from oxidative stress-induced cell death. Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to the mitochondria can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy depletion. These data implicate intra-mitochondrial poly(ADP-ribosylation) as an important therapeutic target for central nervous system and other diseases associated with oxidative stress and energy failure. Poly(ADP-ribosylation), primarily via poly(ADP-ribose) polymerase-1 (PARP-1), is a pluripotent cellular process important for maintenance of genomic integrity and RNA transcription in cells. However, during conditions of oxidative stress and energy depletion, poly(ADP-ribosylation) paradoxically contributes to mitochondrial failure and cell death. Although it has been presumed that poly(ADP-ribosylation) within the nucleus mediates this pathologic process, PARP-1 and other poly(ADP-ribosyltransferases) are also localized within mitochondria. To this end, the presence of PARP-1 and poly(ADP-ribosylation) were verified within mitochondrial fractions from primary cortical neurons and fibroblasts. Inhibition of poly(ADP-ribosylation) within the mitochondrial compartment preserved transmembrane potential (ΔΨm), NAD+content, and cellular respiration, prevented release of apoptosis-inducing factor, and reduced neuronal cell death triggered by oxidative stress. Treatment with liposomal NAD+ also preserved ΔΨm and cellular respiration during oxidative stress. Furthermore, inhibition of poly(ADP-ribosylation) prevented intranuclear localization of apoptosis-inducing factor and protected neurons from excitotoxic injury; and PARP-1 null fibroblasts were protected from oxidative stress-induced cell death. Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to the mitochondria can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy depletion. These data implicate intra-mitochondrial poly(ADP-ribosylation) as an important therapeutic target for central nervous system and other diseases associated with oxidative stress and energy failure. poly(ADP-ribose) polymerase-1 mitochondrial transmembrane potential phosphate-buffered saline 5-iodo-6-amino-1,2-benzyopyrone apoptosis-inducing factor 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide propridium iodide Poly(ADP-ribose) polymerase-1 (PARP-11; EC 2.4.2.30), the most abundant poly(ADP-ribosyltransferase) in mammalian cells, plays an essential role in excitotoxic neuronal death both in vitroand in vivo (1Zhang J. Dawson V.L. Dawson T.M. Snyder S.H. Science. 1994; 263: 687-689Crossref PubMed Scopus (1076) Google Scholar, 2Eliasson M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google mechanism for this in via of of the of PARP-1 in to genomic of NAD+ during the of poly(ADP-ribose) and death via energy failure A. PubMed Scopus Google However, the for PARP-1 within the nucleus to cellular energy compartmentalized within to be Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google Scholar, J. Google in to abundant in cell PARP-1 and other are also in mitochondria P. J. J. PubMed Google Scholar, PubMed Scopus Google Scholar, A. P. J. PubMed Scopus Google to in to oxidative A. J. P. Google Scholar, PubMed Scopus Google that inhibition of mitochondrial poly(ADP-ribosylation) a role in neuronal cell conditions of oxidative stress and that inhibition of mitochondrial poly(ADP-ribosylation) mitochondrial transmembrane potential and NAD+ cellular respiration, and neuronal cell death triggered by oxidative stress Treatment with NAD+ also preserved ΔΨm and cellular respiration, that can also be by energy oxidative stress. suggest that NAD+ and energy failure poly(ADP-ribosylation) compartmentalized within mitochondria from a homeostatic process to a mechanism of neuronal a mechanism by PARP-1 can cell death conditions of mitochondrial and for of These to both and central nervous system diseases oxidative stress is a factor, and and other diseases PubMed Scopus Google Scholar, T.M. Dawson V.L. 3: a of mitochondrial were in and with for were and were with of by and cortical were from to as J. Graham S.H. P.D. Clark R.S. J. 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Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, J. Google these it has been that genomic with cellular NAD+ depletion, by mitochondrial release and and cell death Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google However, data suggest that oxidative stress mitochondrial by of during conditions of mitochondrial NAD+ to energy failure by mitochondrial of inhibition of mitochondrial poly(ADP-ribosylation) and cellular respiration, mitochondrial release of and and cell death oxidative stress. Furthermore, of NAD+ also ΔΨm and cellular These data that inhibition of mitochondrial poly(ADP-ribosylation) and energy to in the of energy and are with the that energy contributes to inhibition has also been to from by oxidative stress K. P. PubMed Scopus Google mitochondrial J. PubMed Google of and within mitochondria P. J. J. PubMed Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. 1997; PubMed Scopus Google Scholar, Wang J. PubMed Scopus Google Scholar, J. PubMed Google the of inhibition to of and within mitochondria are a potential of P. J. PubMed Scopus Google Scholar, PubMed Scopus Google mitochondrial is in conditions of in both of and mitochondrial of PubMed Google Scholar, V.L. Dawson T.M. PubMed Scopus Google of this the of PARP-1 in of cellular NAD+ it is that mitochondrial poly(ADP-ribosylation) contributes in to the of cellular of NAD+ and energy cell death has been to be primarily in (1Zhang J. Dawson V.L. Dawson T.M. Snyder S.H. Science. 1994; 263: 687-689Crossref PubMed Scopus (1076) Google Scholar, 2Eliasson M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, J. Google cell death by has been Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google cell death has of as and by important also as and cell death that inhibition P. A. J. Med. PubMed Scopus Google Scholar, J. P. PubMed Scopus Google Scholar, K. P. J. J. Med. PubMed Scopus Google Scholar, A. PubMed Scopus Google and cell death are to be and that the and neurons from cell death by J. Graham S.H. P.D. Clark R.S. J. PubMed Scopus Google the data that the from cell death by reduced cell death and cell death reduced a in that the of cell death to is K. V. A. PubMed Scopus Google these data suggest the that the of cell death to in that cellular energy P. J. Med. 1997; PubMed Scopus Google Scholar, A. A. Wang Z.Q. K. PubMed Scopus Google inhibition also reduced in fibroblasts to to the also in the cell in to fibroblasts and neurons be to cells, primary cell mitochondrial other these data are with a role for mitochondrial poly(ADP-ribosylation) in cell of during cellular energy are is M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, J. Google it is important to that poly(ADP-ribosylation) homeostatic as to both genomic and mitochondrial PubMed Scopus Google Z.Q. K. 1997; PubMed Scopus Google Scholar, J. PubMed Scopus Google poly(ADP-ribosylation) also a role for transcription and Snyder S.H. A. PubMed Scopus Google and also transcription via A. A. Science. PubMed Scopus Google poly(ADP-ribosylation) within both and mitochondrial as in this homeostatic in cells. poly(ADP-ribosylation) also in A. 1994; PubMed Scopus Google Scholar, A. P. P. A. J. PubMed Google and Dixon C.E. Clark R.S. J. Google as poly(ADP-ribosylation) via A. Science. PubMed Scopus Google Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to both mitochondria and can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy role for mitochondrial poly(ADP-ribosylation) in cell death associated with of mitochondrial and release of is These data that of PARP-1 cellular energy to mitochondrial and cell death. However, these data a poly(ADP-ribosylation) compartmentalized within the mitochondria contributes to release and cell death in the of cellular energy failure. Poly(ADP-ribose) polymerase-1 (PARP-11; EC 2.4.2.30), the most abundant poly(ADP-ribosyltransferase) in mammalian cells, plays an essential role in excitotoxic neuronal death both in vitroand in vivo (1Zhang J. Dawson V.L. Dawson T.M. Snyder S.H. Science. 1994; 263: 687-689Crossref PubMed Scopus (1076) Google Scholar, 2Eliasson M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google mechanism for this in via of of the of PARP-1 in to genomic of NAD+ during the of poly(ADP-ribose) and death via energy failure A. PubMed Scopus Google However, the for PARP-1 within the nucleus to cellular energy compartmentalized within to be Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google Scholar, J. Google in to abundant in cell PARP-1 and other are also in mitochondria P. J. J. PubMed Google Scholar, PubMed Scopus Google Scholar, A. P. J. PubMed Scopus Google to in to oxidative A. J. P. Google Scholar, PubMed Scopus Google that inhibition of mitochondrial poly(ADP-ribosylation) a role in neuronal cell conditions of oxidative stress and that inhibition of mitochondrial poly(ADP-ribosylation) mitochondrial transmembrane potential and NAD+ cellular respiration, and neuronal cell death triggered by oxidative stress Treatment with NAD+ also preserved ΔΨm and cellular respiration, that can also be by energy oxidative stress. suggest that NAD+ and energy failure poly(ADP-ribosylation) compartmentalized within mitochondria from a homeostatic process to a mechanism of neuronal a mechanism by PARP-1 can cell death conditions of mitochondrial and for of These to both and central nervous system diseases oxidative stress is a factor, and and other diseases PubMed Scopus Google Scholar, T.M. Dawson V.L. 3: a of mitochondrial were in and with for were and were with of by and cortical were from to as J. Graham S.H. P.D. Clark R.S. J. 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Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, J. Google these it has been that genomic with cellular NAD+ depletion, by mitochondrial release and and cell death Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google However, data suggest that oxidative stress mitochondrial by of during conditions of mitochondrial NAD+ to energy failure by mitochondrial of inhibition of mitochondrial poly(ADP-ribosylation) and cellular respiration, mitochondrial release of and and cell death oxidative stress. Furthermore, of NAD+ also ΔΨm and cellular These data that inhibition of mitochondrial poly(ADP-ribosylation) and energy to in the of energy and are with the that energy contributes to inhibition has also been to from by oxidative stress K. P. PubMed Scopus Google mitochondrial J. PubMed Google of and within mitochondria P. J. J. PubMed Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. 1997; PubMed Scopus Google Scholar, Wang J. PubMed Scopus Google Scholar, J. PubMed Google the of inhibition to of and within mitochondria are a potential of P. J. PubMed Scopus Google Scholar, PubMed Scopus Google mitochondrial is in conditions of in both of and mitochondrial of PubMed Google Scholar, V.L. Dawson T.M. PubMed Scopus Google of this the of PARP-1 in of cellular NAD+ it is that mitochondrial poly(ADP-ribosylation) contributes in to the of cellular of NAD+ and energy cell death has been to be primarily in (1Zhang J. Dawson V.L. Dawson T.M. Snyder S.H. Science. 1994; 263: 687-689Crossref PubMed Scopus (1076) Google Scholar, 2Eliasson M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, J. Google cell death by has been Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google cell death has of as and by important also as and cell death that inhibition P. A. J. Med. PubMed Scopus Google Scholar, J. P. PubMed Scopus Google Scholar, K. P. J. J. Med. PubMed Scopus Google Scholar, A. PubMed Scopus Google and cell death are to be and that the and neurons from cell death by J. Graham S.H. P.D. Clark R.S. J. PubMed Scopus Google the data that the from cell death by reduced cell death and cell death reduced a in that the of cell death to is K. V. A. PubMed Scopus Google these data suggest the that the of cell death to in that cellular energy P. J. Med. 1997; PubMed Scopus Google Scholar, A. A. Wang Z.Q. K. PubMed Scopus Google inhibition also reduced in fibroblasts to to the also in the cell in to fibroblasts and neurons be to cells, primary cell mitochondrial other these data are with a role for mitochondrial poly(ADP-ribosylation) in cell of during cellular energy are is M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, J. Google it is important to that poly(ADP-ribosylation) homeostatic as to both genomic and mitochondrial PubMed Scopus Google Z.Q. K. 1997; PubMed Scopus Google Scholar, J. PubMed Scopus Google poly(ADP-ribosylation) also a role for transcription and Snyder S.H. A. PubMed Scopus Google and also transcription via A. A. Science. PubMed Scopus Google poly(ADP-ribosylation) within both and mitochondrial as in this homeostatic in cells. poly(ADP-ribosylation) also in A. 1994; PubMed Scopus Google Scholar, A. P. P. A. J. PubMed Google and Dixon C.E. Clark R.S. J. Google as poly(ADP-ribosylation) via A. Science. PubMed Scopus Google Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to both mitochondria and can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy role for mitochondrial poly(ADP-ribosylation) in cell death associated with of mitochondrial and release of is These data that of PARP-1 cellular energy to mitochondrial and cell death. However, these data a poly(ADP-ribosylation) compartmentalized within the mitochondria contributes to release and cell death in the of cellular energy failure. poly(ADP-ribosylation) contributes to cell inhibition of during conditions of cellular energy failure oxidative is M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, J. Google these it has been that genomic with cellular NAD+ depletion, by mitochondrial release and and cell death Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google However, data suggest that oxidative stress mitochondrial by of during conditions of mitochondrial NAD+ to energy failure by mitochondrial of inhibition of mitochondrial poly(ADP-ribosylation) and cellular respiration, mitochondrial release of and and cell death oxidative stress. Furthermore, of NAD+ also ΔΨm and cellular These data that inhibition of mitochondrial poly(ADP-ribosylation) and energy to in the of energy and are with the that energy contributes to inhibition has also been to from by oxidative stress K. P. PubMed Scopus Google mitochondrial J. PubMed Google of and within mitochondria P. J. J. PubMed Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. 1997; PubMed Scopus Google Scholar, Wang J. PubMed Scopus Google Scholar, J. PubMed Google the of inhibition to of and within mitochondria are a potential of P. J. PubMed Scopus Google Scholar, PubMed Scopus Google mitochondrial is in conditions of in both of and mitochondrial of PubMed Google Scholar, V.L. Dawson T.M. PubMed Scopus Google of this the of PARP-1 in of cellular NAD+ it is that mitochondrial poly(ADP-ribosylation) contributes in to the of cellular of NAD+ and energy failure. cell death has been to be primarily in (1Zhang J. Dawson V.L. Dawson T.M. Snyder S.H. Science. 1994; 263: 687-689Crossref PubMed Scopus (1076) Google Scholar, 2Eliasson M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, J. Google cell death by has been Wang Dawson T.M. Dawson V.L. Science. PubMed Scopus Google cell death has of as and by important also as and cell death that inhibition P. A. J. Med. PubMed Scopus Google Scholar, J. P. PubMed Scopus Google Scholar, K. P. J. J. Med. PubMed Scopus Google Scholar, A. PubMed Scopus Google and cell death are to be and that the and neurons from cell death by J. Graham S.H. P.D. Clark R.S. J. PubMed Scopus Google the data that the from cell death by reduced cell death and cell death reduced a in that the of cell death to is K. V. A. PubMed Scopus Google these data suggest the that the of cell death to in that cellular energy P. J. Med. 1997; PubMed Scopus Google Scholar, A. A. Wang Z.Q. K. PubMed Scopus Google inhibition also reduced in fibroblasts to to the also in the cell in to fibroblasts and neurons be to cells, primary cell mitochondrial other these data are with a role for mitochondrial poly(ADP-ribosylation) in cell death. of during cellular energy are is M.J. Sampei K. Mandir A.S. Hurn P.D. Traystman R.J. Bao J. Pieper A. Wang Z.Q. Dawson T.M. Snyder S.H. Dawson V.L. Nat. Med. 1997; 3: 1089-1095Crossref PubMed Scopus (939) Google Scholar, 3Whalen M.J. Clark R.S. Dixon C.E. Robichaud P. Marion D.W. Vagni V. Graham S.H. Virag J. PubMed Scopus Google Scholar, J. Google it is important to that poly(ADP-ribosylation) homeostatic as to both genomic and mitochondrial PubMed Scopus Google Z.Q. K. 1997; PubMed Scopus Google Scholar, J. PubMed Scopus Google poly(ADP-ribosylation) also a role for transcription and Snyder S.H. A. PubMed Scopus Google and also transcription via A. A. Science. PubMed Scopus Google poly(ADP-ribosylation) within both and mitochondrial as in this homeostatic in cells. poly(ADP-ribosylation) also in A. 1994; PubMed Scopus Google Scholar, A. P. P. A. J. PubMed Google and Dixon C.E. Clark R.S. J. Google as poly(ADP-ribosylation) via A. Science. PubMed Scopus Google Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to both mitochondria and can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy depletion. role for mitochondrial poly(ADP-ribosylation) in cell death associated with of mitochondrial and release of is These data that of PARP-1 cellular energy to mitochondrial and cell death. However, these data a poly(ADP-ribosylation) compartmentalized within the mitochondria contributes to release and cell death in the of cellular energy failure. are to and for mitochondrial for of the and for