Period 3 regulates mitochondrial function via the NAD+-SIRT3 axis in mice

Abstract Mitochondrial fission-fusion dynamics and bioenergetics are strongly clock-controlled. However, the mechanistic relationship between the clock and mitochondrial function remains largely unknown. Here we revealed that the clock gene Per3 plays an essential role in the maintenance of mitochondrial homeostasis. Both in vitro and in vivo deletion of Per3 consistently led to the disrupted mitochondrial integrity, including decreased mitochondrial membrane potential, impaired fission-fusion dynamics, increased oxidative stress, and altered mitochondrial bioenergetics. Mechanistically, we showed the binding of PER3 and BMAL1 to E-box regulatory elements in the promoter region of the nicotinamide phosphoribosyltransferase (NAMPT) gene promoted the gene activation as well as increased the NAMPT-dependent NAD+ generation, which in turn induced the enzymatic activity of mitochondrial deacetylase SIRT3. Interestingly, administering nicotinamide mononucleotide (NAM), an NAD+ precursor, protected cells from the Per3 deletion-induced NAD+ decline and associated mitochondrial dysfunction, whereas blocking of SIRT3’s acetylation activity with 3-(1H-1, 2, 3-triazol-4-yl) pyridine abolished this beneficial effect of NAM on the global mitochondrial protein acetylation and homeostasis mechanisms. Collectively, we demonstrate that Per3 maintains mitochondrial integrity by regulating NAD+-dependent SIRT3 activity and highlight a critical role for PER3 in mitochondrial homeostatic function.