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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.