Role of Mitochondrial damage-associated molecular patterns in osteoarthritis: from pathogenesis, diagnosis, and prognosis to therapeutics
Jiayi Cai, Z H Chen, Xinhan Yang, Jing Cai, Linxin Chen, Sihang Chen, Yuchun Zou, Dali Zheng, Linyu Xu
Abstract
Osteoarthritis (OA) is a debilitating disease, that imposes a heavy burden on individuals, society, and the healthcare systems. Despite extensive research, the precise pathogenesis of OA remains incompletely defined, hindering the development of targeted therapies. Elucidating OA's molecular mechanisms is fundamental to precision medicine, as it enables identification of diagnostic and prognostic biomarkers while informing tailored treatment strategies. Current clinical guidelines prioritize conservative, non-invasive approaches, however, these demonstrate limited efficacy in halting or reversing disease progression. Within this context, mitochondrial dysfunction has emerged as a critical pathological driver in OA. Specifically, abnormal release of mitochondrial metabolites and components-functioning as damage-associated molecular patterns (mtDAMPs)-triggers inflammatory cascades that accelerate joint degeneration. These mtDAMPs additionally serve as dynamic biomarkers, with their release kinetics correlating with structural deterioration severity. Consequently, mitochondria-targeted therapies restoring mitochondrial quality control represent promising disease-modifying interventions. Here we discuss the origins and roles of key mtDAMPs (mtROS/mtDNA) in OA pathogenesis; their diagnostic and prognostic utility; and therapeutic strategies targeting mitochondrial homeostasis to mitigate OA progression.