PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation Academic Article uri icon

Overview

MeSH Major

  • Mitochondria
  • Poly(ADP-ribose) Polymerases
  • Sirtuin 1

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.

publication date

  • April 6, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3086520

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2011.03.004

PubMed ID

  • 21459330

Additional Document Info

start page

  • 461

end page

  • 8

volume

  • 13

number

  • 4