Sirtuin 5-mediated desuccinylation of Slc25a4 inhibits osteoporosis by enhancing mitochondrial respiration.

Osteoporosis is a prevalent metabolic bone disorder that develops when osteoclast-mediated bone resorption chronically exceeds osteoblast-driven bone formation. The molecular pathways that govern osteogenic dysfunction and connect cellular metabolism to differentiation regulation remain poorly characterized. Here, we identify Sirtuin 5 (Sirt5) as a pivotal osteogenic regulator through bioinformatic screening and functional validation in Sirt5-knockout mice. Mechanistically, Sirt5 governs mitochondrial homeostasis by desuccinylating Solute Carrier Family 25 Member 4 (Slc25a4) at lysine 147 (K147), as demonstrated by quantitative succinylome profiling and site-directed mutagenesis. This site-specific desuccinylation triggers Slc25a4 degradation, attenuating mitochondrial oxidative stress and promoting osteoblast differentiation. Crucially, Slc25a4-K147 succinylation drives osteoporosis progression, while Sirt5-mediated desuccinylation at this site confers protection. Our work reveals the Sirt5-Slc25a4-K147 axis as a novel regulatory mechanism coupling mitochondrial metabolism to bone homeostasis, offering a therapeutic target for osteoporosis intervention.