PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation

Péter Bai, Carles Cantó, Hugues Oudart, Attila Brunyánszki, Yana Cen, Charles Thomas, Hiroyasu Yamamoto, Aline Huber, Borbála Kiss, Riekelt H. Houtkooper, Kristina Schoonjans, Valérie Schreiber, Anthony A. Sauve, Josiane Menissier-De Murcia, Johan Auwerx

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427 Citations (Scopus)

Abstract

SIRT1 regulates energy homeostasis by controlling the acetylation status and activity of a number of enzymes and transcriptional regulators. The fact that NAD+ levels control SIRT1 activity confers a hypothetical basis for the design of new strategies to activate SIRT1 by increasing NAD+ availability. Here we show that the deletion of the poly(ADP-ribose) polymerase-1 (PARP-1) gene, encoding a major NAD+-consuming enzyme, increases NAD+ content and SIRT1 activity in brown adipose tissue and muscle. PARP-1-/- mice phenocopied many aspects of SIRT1 activation, such as a higher mitochondrial content, increased energy expenditure, and protection against metabolic disease. Also, the pharmacologic inhibition of PARP in vitro and in vivo increased NAD+ content and SIRT1 activity and enhanced oxidative metabolism. These data show how PARP-1 inhibition has strong metabolic implications through the modulation of SIRT1 activity, a property that could be useful in the management not only of metabolic diseases, but also of cancer.

Original languageEnglish
Pages (from-to)461-468
Number of pages8
JournalCell Metabolism
Volume13
Issue number4
DOIs
Publication statusPublished - Apr 6 2011

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., Thomas, C., Yamamoto, H., Huber, A., Kiss, B., Houtkooper, R. H., Schoonjans, K., Schreiber, V., Sauve, A. A., Menissier-De Murcia, J., & Auwerx, J. (2011). PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metabolism, 13(4), 461-468. https://doi.org/10.1016/j.cmet.2011.03.004