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STOML2 Alleviates Osteoarthritis by Regulating Mitochondrial Energy Metabolism and Oxidative Stress
1Department of Orthopaedics, Fuzhou Second General Hospital, Fuzhou, 350007, China.
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.
Insights
Stomatin-like protein 2 (STOML2) is crucial for maintaining mitochondrial health in osteoarthritis (OA). Restoring STOML2 function protects cartilage cells and reduces OA progression, highlighting STOML2 as a potential therapeutic target.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- Osteoarthritis Pathogenesis
Background:
- Osteoarthritis (OA) involves chondrocyte dysfunction and cartilage degradation.
- Mechanisms maintaining mitochondrial homeostasis during OA progression are not fully understood.
Purpose of the Study:
- Investigate the role of Stomatin-like protein 2 (STOML2) in OA.
- Elucidate the STOML2-mediated pathways governing mitochondrial function and chondrocyte viability.
Main Methods:
- Assessed STOML2 expression in IL-1β-stimulated chondrocytes and human OA cartilage.
- Examined the impact of STOML2 depletion on mitochondrial function (oxidative phosphorylation, ROS).
- Investigated STOML2 interaction with mitochondrial Na+/Ca2+ exchanger (NCLX) and its effect on Ca2+ handling.
- Evaluated STOML2 delivery in a rat OA model.
Main Results:
- STOML2 is downregulated in OA conditions.
- STOML2 depletion leads to impaired oxidative phosphorylation, increased mitochondrial ROS, chondrocyte senescence, and ferroptosis.
- STOML2 interacts with NCLX, supporting mitochondrial Ca2+ efflux and metabolic stability.
- Restoring STOML2 improves Ca2+ handling, reduces mitochondrial Ca2+ overload, mitigates glycolytic shift, and enhances ATP production.
- Intra-articular STOML2 delivery attenuated cartilage degeneration and joint inflammation in rats.
Conclusions:
- STOML2 is essential for maintaining mitochondrial Ca2+ homeostasis and chondrocyte viability in OA.
- The STOML2-NCLX axis represents a novel mechanism safeguarding mitochondrial function.
- STOML2 emerges as a promising therapeutic target for osteoarthritis treatment.
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