Figure 5.

NAD⁺ boosts mitophagy. Cellular NAD⁺ could be complemented by food supplementation of the metabolic precursors including NAM, NR and NMN, or synthesized de novo. SIRTs and PARPs are two major NAD⁺-dependent enzymes catalyzing the NAD⁺ to yield NAM, which is gradually elevated during aging, DNA damage and other genetic or environmental insults. NAD⁺ is imported into mitochondria to sustain several mitochondrial metabolisms. It was reported that NAD⁺ facilitates mitochondrial biogenesis via SIRTs-PPARGC1A axis. Additionally, NAD⁺ activates AMPK kinase through supporting SIRTs deacetylation of STK11, or through ATM-STK11-AMPK or ATM-AMPK axes. Alternatively, the activated SIRTs could mediate deacetylation of autophagy core components MAP1LC3, ATG5 and ATG7, as well as deacetylation of FOXOs to promote the expression of BNIP3, MAP1LC3 and ATGs, or enhance PINK1 stabilization, which collaboratively strengthen the mitophagy program.