Targeting the mitochondrial metabolite-dynamics-MDVs-MitoEVs axis: a new frontier in osteoarthritis management

BACKGROUND: Osteoarthritis (OA) is characterized by progressive cartilage degradation, osteophyte formation, and synovitis. OA progression is linked to mitochondrial metabolic dysfunction, marked by tricarboxylic acid (TCA) cycle imbalance and impaired oxidative phosphorylation (OXPHOS). KEY SCIENTIFIC CONCEPTS OF REVIEW: Three critical factors regulate mitochondrial metabolism: mitochondrial metabolites, mitochondrial dynamics, and mitochondrial-derived vesicles (MDVs). Mitochondrial metabolites such as fumarate and succinate exacerbate OA pathogenesis by mediating mitochondrial dysfunction, whereas itaconate, α-ketoglutarate (α-KG), and fumarate derivatives confer protective effects. Imbalanced mitochondrial dynamics drive cartilage degradation through oxidative stress. Inflammatory MDVs may accelerate OA by transferring mitochondrial damage-associated molecular patterns (mtDAMPs) into the extracellular space through mitochondrial-derived extracellular vesicles (mitoEVs). Given the interplay of mitochondrial metabolites, mitochondrial dynamics, and MDVs/mitoEVs, we propose that the metabolite-dynamics-MDVs-mitoEVs axis represents a pivotal mechanism driving OA progression and a potential target for mitochondrial-directed therapies. CONCLUSION: Future efforts should prioritize advancing mitochondrial metabolic modulators and MSC-mitoEVs, with validation through synovial fluid biomarkers and support from crucial preclinical safety and delivery studies.