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.
Around 2 billion years ago, eukaryotes evolved by integrating a bacterial precursor of modern mitochondria, which still contain essential molecules for cell survival. Understanding these pathways is crucial for treating diseases like cancer and neurodegeneration. A major cause of cell death from genotoxic stress is the hyperactivation of the NAD+-dependent enzyme PARP-1, leading to apoptosis. Recent findings suggest mitochondrial NAD+ could influence cell fate, though much remains unknown about its biosynthesis and concentration.
Sirtuins, a family of NAD+-dependent enzymes, are key regulators of cell survival and longevity. In yeast, Sir2 extends lifespan under stress and calorie restriction, and its mammalian counterparts, including SIRT1 and mitochondrial sirtuins SIRT3-5, play similar roles. The yeast gene PNC1 aids NAD+ biosynthesis and may have a mammalian equivalent in Nampt, which enhances SIRT1 activity and protects cells from PARP-induced death.
This paper identifies NAMPT as a gene that increases mitochondrial NAD+ levels, showing that fasting boosts NAMPT expression and mitochondrial NAD+. The study reveals that higher mitochondrial NAD+ enhances cell survival during genotoxic stress, mediated by SIRT3 and SIRT4, highlighting the role of mitochondrial NAD+ in apoptosis and the impact of diet on health and disease.
