FASEB J. Pierce now sold as Thermo Scientific
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by SCOVASSI, A. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by SCOVASSI, A. I.
(The FASEB Journal. 2004;18:1487-1488.)
© 2004 FASEB

Mitochondrial poly(ADP-ribosylation): from old data to new perspectives

A. IVANA SCOVASSI1

Istituto di Genetica Molecolare CNR, Pavia, Italy

1Correspondence: Via Abbiategrasso 207, Pavia, Italy 27100. E-mail: scovassi{at}igm.cnr.it


   ABSTRACT
TOP
 ABSTRACT
REFERENCES
 
Poly(ADP-ribosylation) is involved in DNA repair and replication, transcription, and cell death. For a long time, only one poly(ADP-ribosylating) enzyme was known, named ADPRT/PARP (EC 2.4.2.30). The recent discovery of a family of PARPs has provided a high degree of complexity in the field. Moreover, the finding that poly(ADP-ribosylation) is not confined to the nucleus but is also carried out by cytoplasmic enzymes supports the idea that it could regulate proteins localized in different cellular compartments. In this respect, a reappraisal of the literature on mitochondrial poly(ADP-ribosylation) could be useful, as well as a discussion of its relevance regarding the current "hot" view of poly(ADP-ribosylation) as a mediator of cell death.—Scovassi, A. I. Mitochondrial poly(ADP-ribosylation): from old data to new perspectives.


Key Words: mitochondria • cell death • ROS • cytoplasmic enzyme • poly(ADP-ribosylate)

AMONG THE post-translational modifications of proteins, poly(ADP-ribosylation) plays a crucial role in regulating DNA repair and replication, transcription, and cell death (1) . This biochemical reaction was discovered 40 years ago in the nucleus of eukaryotic cells (2) . For a long time, only one poly(ADP-ribosylating) enzyme was known, named ADPRT or PARP (EC 2.4.2.30); more recently, a family of enzymes able to convert the substrate NAD+ into ADP-ribose and to bind polymers of ADP-ribose on acceptor proteins has been described that is not confined to the nucleus (3) . At this time it might be appropriate to attempt to reconcile earlier biochemical observations with recent reports suggesting that poly(ADP-ribosylation) regulates the activity and function of proteins localized in different cellular compartments, including mitochondria.

A great amount of cellular NAD+ is located within the mitochondria, where it represents the substrate for mono(ADP-ribosylation) reactions and for the formation of cyclic (ADP-ribose) (4) ; moreover, many groups have been actively involved in the search for a mitochondrial poly(ADP-ribosylation). In 1977, Hayaishi and Ueda reviewed the data on poly(ADP-ribosylation) (5) and affirmed that a significant cellular potential for ADP-ribosylation exists outside the nucleus and in mitochondria, as reported by Kun et al. (6) , who found that these organelles synthesize ADP-ribose from NAD+ and ADP-ribosylate a mitochondrial protein of 100 kDa. Further searches for the presence of enzymatic activity able to catalyze the transfer of single or oligo-ADP-ribose to mitochondrial proteins were successful in rat liver (7 , 8) , brain (9) , and testis (10) , analyzed with classical biochemical procedures. A student from our laboratory applied an activity gel assay (11) to mouse liver and chick embryo mitochondria isolated with a validated procedure (12) that prevents possible nuclear contamination of the mitochondrial pellet. In her graduation thesis (13) , Warnsing described a mitochondrial PARP of ~110 kDa that is able to automodify itself; however, the general skeptical attitude toward mitochondrial poly(ADP-ribosylation) discouraged us from publishing these data.

To my mind, the transition from the "obscurantist" to the "illuministic" view of mitochondrial poly(ADP-ribosylation) was marked by the ultrastructural analysis of the intracellular distribution of PARP, suggestive of its presence in HeLa and Sertoli cell mitochondria (14) . As for the physiological function of mitochondrial poly(ADP-ribosylation), a good reason to postulate its active role is the existence of a base excision repair (BER) pathway for repairing mitochondrial DNA damage, possibly involving the same factors as nuclear BER, including PARP-1 (15) . Indeed, it was shown that under conditions of damage to mitochondrial DNA induced by a diabetogen-alkylating agent, poly(ADP-ribosylation) facilitates DNA repair (16) . Furthermore, endogenous reactive oxygen species (ROS) produced during aging induce breaks in mitochondrial DNA and require the activation of both nuclear and mitochondrial ADP-ribosylation processes for efficient DNA repair (17) .

Researchers in the apoptosis field know that excessive poly(ADP-ribosylation) is responsible for NAD+ consumption and that PARP-1 regulates apoptotic DNA degradation by modifying a specific endonuclease (reviewed in ref 18). An interesting functional correlation between poly(ADP-ribosylation) and cell death machinery was suggested by the observation that PARP-1 mediates the release of AIF (apoptosis-inducing factor) and its shuttling from mitochondria to the nucleus, with consequent activation of a caspase-independent apoptotic pathway (19 , 20) . Among the possible mechanisms leading to AIF regulation by PARP-1, a direct interaction between these proteins cannot be excluded (21) . In fact, recent data showed an intramitochondrial poly(ADP-ribosylation) in primary rat cortical neurons and mouse fibroblasts, where AIF release (and, in turn, apoptosis) can be prevented by PARP inhibitors (22) . Based on this evidence, the inhibition of poly(ADP-ribosylation)-mediated AIF activity might represent a strategy to modulate energy-dependent cell death (23) , in line with the more general therapeutic effect of PARP inhibitors (24) . New data in this direction could help to go deeper into the definition of the pathophysiological relevance of mitochondrial NAD+ metabolism (4 , 25) .

A last enigma to solve is how PARP protein(s) [and maybe PARG, the glycohydrolase that degrades poly(ADP-ribose)] could be shuttled into mitochondria. The mitochondrial import job is done by translocation machineries mainly involving TOM/TIM factors (26) , among which TIM 23 shares a common promoter region with the gene for human PARG (27) . This is a major challenge for understanding the molecular mechanisms leading to mitochondrial poly(ADP-ribosylation).

This story is an example of how biochemical data can be unappreciated for years, until functional studies suggest their physiological meaning. The scientific community working in the poly(ADP-ribosylation) field has made a great effort to define the structural and functional properties of this biochemical reaction. The current "hot" view of poly(ADP-ribosylation) as a mediator of cell death attributes to this process a precise role in regulating crucial cellular responses, and identifies a strategy for its beneficial modulation.


   ACKNOWLEDGMENTS
 
The above considerations about past and present research on mitochondrial poly(ADP-ribosylation) have been stimulated by active discussions during the XVI Meeting of the Italian Group "ADPribosylation Processes" held last September in Pavia. The encouragement of the members of this group (http://www.adpr.unina.it) is kindly acknowledged. Special thanks are due to Umberto Bertazzoni and to our frustrated student, Petra Warnsing. Work in the author’s laboratory is supported by the Italian CNR and MIUR (FIRB Project RBNE0132MY).

Received for publication May 13, 2004. Accepted for publication June 16, 2004.


   REFERENCES
TOP
 ABSTRACT
 REFERENCES
 

  1. Bürkle, A. (2001) Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays 23,795-806[CrossRef][Medline]
  2. Chambon, P., Weill, J. D., Mandel, P. (1963) Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem. Biophys. Res. Commun. 11,39-43[CrossRef][Medline]
  3. Chiarugi, A. (2002) Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol. Sci. 23,122-129[CrossRef][Medline]
  4. Di Lisa, F., Ziegler, M. (2001) Pathophysiological relevance of mitochondria in NAD+ metabolism. FEBS Lett. 492,4-8[CrossRef][Medline]
  5. Hayaishi, O., Ueda, K. (1977) Poly(ADP-ribose) and ADP-ribosylation of proteins. Annu. Rev. Biochem. 46,95-116[CrossRef][Medline]
  6. Kun, E., Zimber, P. H., Chang, A. C. Y., Puschendorf, B., Grunicke, H. (1975) Macromolecular enzymatic product of NAD+ in liver mitochondria. Proc. Natl. Acad. Sci. USA 72,1436-1440[Abstract/Free Full Text]
  7. Richter, C., Winterhalter, K. H., Baumhuter, S., Lotscher, H. R., Moser, B. (1983) ADP-ribosylation in inner membrane of rat liver mitochondria. Proc. Natl. Acad. Sci. USA 80,3188-3192[Abstract/Free Full Text]
  8. Masmoudi, A., Mandel, P. (1987) ADP-ribosyl transferase and NAD glycohydrolase activities in rat liver mitochondria. Biochemistry 26,1965-1969[CrossRef][Medline]
  9. Masmoudi, A., Islam, F., Mandel, P. (1988) ADP-ribosylation of highly purified rat brain mitochondria. J. Neurochem. 51,188-193[CrossRef][Medline]
  10. Burzio, L. O., Saez, L., Cornejo, R. (1981) Poly (ADP-ribose) synthetase activity in rat testis mitochondria. Biochem. Biophys. Res. Commun. 103,369-375[CrossRef][Medline]
  11. Scovassi, A. I., Stefanini, M., Bertazzoni, U. (1984) Catalytic activities of human poly(ADP-ribose) polymerase from normal and mutagenized cells detected after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. J. Biol. Chem. 259,10973-10977[Abstract/Free Full Text]
  12. Bertazzoni, U., Scovassi, A. I., Brun, G. M. (1977) Chick-embryo DNA polymerase {gamma}. Identity of {gamma}-polymerases purified from nuclei and mitochondria. Eur. J. Biochem. 81,237-248[Medline]
  13. Warnsing, P. (1986) Analisi e caratterizzazione della ADP-ribosio transferasi in mitocondri di fegato di topo e embrioni di pollo, Graduation thesis University of Pavia Italy.
  14. Mosgoeller, W., Steiner, M., Hozak, P., Penner, E., Wesierska-Gadek, J. (1996) Nuclear architecture and ultrastructural distribution of poly(ADP-ribosyl)transferase, a multifunctional enzyme. J. Cell Sci. 109,409-418[Abstract]
  15. Dantzer, F., Schreiber, V., Niedergang, C., Trucco, C., Flatter, E., De La Rubia, G., Oliver, J., Rolli, V., Ménissier-de Murcia, J., de Murcia, G. (1999) Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 81,69-75[Medline]
  16. Druzhyna, N., Smulson, M. E., LeDoux, S. P., Wilson, G. L. (2000) Poly(ADP-ribose) polymerase facilitates the repair of N-methylpurines in mitochondrial DNA. Diabetes 49,1849-1855[Abstract]
  17. Spina Purrello, V., Cormaci, G., Denaro, L., Reale, S., Costa, A., Lalicata, C., Sabbatini, M., Marchetti, B., Avola, R. (2002) Effect of growth factors on nuclear and mitochondrial ADP-ribosylation processes during astroglial cell development and aging in culture. Mech. Ageing Dev. 123,511-520[CrossRef][Medline]
  18. Scovassi, A. I., Torriglia, A. (2003) Activation of DNA-degrading enzymes during apoptosis. Eur. J. Histochem 47,185-194[Medline]
  19. Yu, S. W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297,259-263[Abstract/Free Full Text]
  20. Hong, S. J., Dawson, T. M., Dawson, V. L. (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol. Sci. 25,259-264[CrossRef][Medline]
  21. Cregan, S. P., Dawson, V. L., Slack, R. S. (2004) Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 23,2785-2796[CrossRef][Medline]
  22. Du, L., Zhang, X., Han, Y. Y., Burke, N. A., Kochanek, P. M., Watkins, S. C., Graham, S. H., Carcillo, J. A., Szabó, C., Clark, R. S. B. (2003) Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. J. Biol. Chem. 278,18426-18433[Abstract/Free Full Text]
  23. Klaidman, L. K., Yang, Y., Chang, M. L., Adams, J. D., Jr (2003) Recent developments on the role of mitochondria in poly(ADP-ribose) polymerase inhibition. Curr. Med. Chem. 10,2669-2678[CrossRef][Medline]
  24. Virág, L., Szabó, C. (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol. Rev. 54,375-429[Abstract/Free Full Text]
  25. Berger, F., Ramirez-Hernandez, M. H., Ziegler, M. (2004) The new life of a centenarian: signaling functions of NAD(P). Trends Biochem. Sci. 29,111-118[CrossRef][Medline]
  26. Wiedemann, N., Frazier, A. E., Pfanner, N. (2004) The protein import machinery of mitochondria. J. Biol. Chem. 279,14473-14476[Free Full Text]
  27. Meyer, R. G., Meyer-Ficca, M. L., Jacobson, E. L., Jacobson, M. K. (2003) Human poly(ADP-ribose) glycohydrolase (PARG) gene and the common promoter sequence it shares with inner mitochondrial membrane translocase 23 (TIM23). Gene 314,181-190[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Mol. Cell. Biol.Home page
M. Niere, S. Kernstock, F. Koch-Nolte, and M. Ziegler
Functional Localization of Two Poly(ADP-Ribose)-Degrading Enzymes to the Mitochondrial Matrix
Mol. Cell. Biol., January 15, 2008; 28(2): 814 - 824.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
M.-P. Egloff, H. Malet, A. Putics, M. Heinonen, H. Dutartre, A. Frangeul, A. Gruez, V. Campanacci, C. Cambillau, J. Ziebuhr, et al.
Structural and Functional Basis for ADP-Ribose and Poly(ADP-Ribose) Binding by Viral Macro Domains.
J. Virol., September 1, 2006; 80(17): 8493 - 8502.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Cipriani, E. Rapizzi, A. Vannacci, R. Rizzuto, F. Moroni, and A. Chiarugi
Nuclear Poly(ADP-ribose) Polymerase-1 Rapidly Triggers Mitochondrial Dysfunction
J. Biol. Chem., April 29, 2005; 280(17): 17227 - 17234.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by SCOVASSI, A. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by SCOVASSI, A. I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS