Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.
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.
Yang
Hongying
H
Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Yang
Tianle
T
Baur
Joseph A
JA
Perez
Evelyn
E
Matsui
Takashi
T
Carmona
Juan J
JJ
Lamming
Dudley W
DW
Souza-Pinto
Nadja C
NC
Bohr
Vilhelm A
VA
Rosenzweig
Anthony
A
de Cabo
Rafael
R
Sauve
Anthony A
AA
Sinclair
David A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005508:Food Deprivation; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D056566:Sirtuin 3; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection; D015854:Up-Regulation
D016207:Cytokines; D024101:Mitochondrial Proteins; D009153:Mutagens; D034741:RNA, Small Interfering; D009243:NAD; D008741:Methyl Methanesulfonate; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C495867:nicotinamide phosphoribosyltransferase, mouse; C504970:nicotinamide phosphoribosyltransferase, rat; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D037761:Sirtuins