STOML2 Alleviates Osteoarthritis by Regulating Mitochondrial Energy Metabolism and Oxidative Stress

Abstract

Osteoarthritis (OA) is associated with chondrocyte dysfunction and cartilage degeneration, but how mitochondrial homeostasis is maintained during OA progression remains incompletely understood. Here, we show that Stomatin-like protein 2 (STOML2) is downregulated in IL-1β-stimulated chondrocytes and in human OA cartilage. STOML2 depletion impairs oxidative phosphorylation, elevates mitochondrial reactive oxygen species, and promotes chondrocyte senescence and ferroptotic cell death. Mechanistically, STOML2 interacts with the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) to support mitochondrial Ca²⁺ efflux and metabolic stability. Restoring STOML2 enhances NCLX-dependent Ca²⁺ handling, mitigates mitochondrial Ca²⁺ overload and the glycolytic shift, and improves ATP production. In a rat OA model, intra-articular delivery of STOML2 attenuates cartilage degeneration and reduces inflammatory changes in the joint. Together, these findings identify a STOML2-NCLX axis that safeguards mitochondrial Ca²⁺ homeostasis and chondrocyte viability, suggesting STOML2 as a potential therapeutic target for OA.

Keywords: STOML2; mitochondrial dysfunction; osteoarthritis; oxidative stress.