Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival

Cell. 2007 Sep 21;130(6):1095-107. doi: 10.1016/j.cell.2007.07.035.

Abstract

A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD(+) from the nucleus and the cytoplasm. Here we show that NAD(+) levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD(+) are depleted. Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+). Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD(+) salvage pathway as well as the mitochondrial NAD(+)-dependent deacetylases SIRT3 and SIRT4. We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cell Hypoxia
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cytokines / biosynthesis*
  • Cytokines / metabolism*
  • Cytoplasm / metabolism
  • Fasting / metabolism*
  • Food Deprivation
  • Humans
  • Methyl Methanesulfonate / toxicity
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mutagens / toxicity
  • NAD / metabolism*
  • Nicotinamide Phosphoribosyltransferase
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Sirtuin 3
  • Sirtuins / genetics
  • Sirtuins / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transfection
  • Up-Regulation

Substances

  • Cytokines
  • Mitochondrial Proteins
  • Mutagens
  • RNA, Small Interfering
  • NAD
  • Methyl Methanesulfonate
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • nicotinamide phosphoribosyltransferase, mouse
  • nicotinamide phosphoribosyltransferase, rat
  • SIRT3 protein, human
  • Sirtuin 3
  • Sirtuins