Energy Stress, NAD+-Dependent UPRmt Signaling, and Mitochondrial Health
The aging process and associated metabolic diseases, including obesity and mitochondrial diseases, can be improved in mice and C. elegans using NAD+ boosters or PARP/CD38 inhibitors (PARPi/CD38i) in much the same way as has been demonstrated by CR. Part of the metabolic decline during aging is due to a PARP-directed reduction in NAD+ levels, attenuating SIRT1 and FOXO3A activities and leading to the activation of HIF1α and an increased reliance on glycolysis. Recently, a mechanism has been proposed for these NAD+-mediated improvements that include the induction of the UPRmt, which is triggered by SIRT1- and SIRT3-induced mitochondrial biogenesis, creating an imbalance in mitochondrial- versus nuclear-encoded mitochondrial proteins. This mitonuclear imbalance activates the UPRmt, a retrograde signal that induces a mitohormetic and adaptive nuclear response, ultimately repairing and improving mitochondrial function. These mitohormetic signals can attenuate the impact of aging, mitochondrial diseases, or a HFD on metabolism.