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
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis* / drug effects
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Cell Hypoxia
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Cell Line
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Cell Nucleus / metabolism
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Cell Survival
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Cells, Cultured
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Cytokines / biosynthesis*
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Cytokines / metabolism*
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Cytoplasm / metabolism
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Fasting / metabolism*
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Food Deprivation
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Humans
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Methyl Methanesulfonate / toxicity
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Mice
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Mitochondria / drug effects
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Mitochondria / enzymology
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Mitochondria / metabolism*
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Mitochondria / pathology
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mutagens / toxicity
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NAD / metabolism*
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Nicotinamide Phosphoribosyltransferase
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RNA Interference
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RNA, Small Interfering / metabolism
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Rats
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Sirtuin 3
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Sirtuins / genetics
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Sirtuins / metabolism
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Transfection
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Up-Regulation
Substances
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Cytokines
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Mitochondrial Proteins
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Mutagens
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RNA, Small Interfering
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NAD
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Methyl Methanesulfonate
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human
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nicotinamide phosphoribosyltransferase, mouse
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nicotinamide phosphoribosyltransferase, rat
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SIRT3 protein, human
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Sirtuin 3
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Sirtuins