Musculoskeletal disorders (MSDs), including osteoporosis (OP), osteoarthritis (OA), and rheumatoid arthritis (RA), represent a stubborn burden in modern medicine. They share a breakdown in mitochondrial homeostasis. Mitochondrial dysfunction serves as a central pathogenic mechanism unifying these conditions and driving a paradigm shift from symptomatic management to mechanism-based therapeutic strategies. In this review, we examine how mitochondrial defects affect key cell types in bone, cartilage, and muscle, including osteoblasts, osteocytes, osteoclasts, chondrocytes, and skeletal muscle cells, with a focus on osteoporosis (OP), osteoarthritis (OA), and rheumatoid arthritis (RA) as the three primary musculoskeletal conditions that share mitochondrial dysfunction as a unifying mechanism. Impaired energy production, altered dynamics, defective quality control, and redox imbalance each contribute to disease progression. These disturbances drive oxidative damage, metabolic reprogramming, impaired mitophagy, and the release of pro-inflammatory signals known as mtDAMPs. Importantly, such defects are not irreversible, we further synthesize the emerging landscape of mitochondria-targeted strategies. These include antioxidants like MitoQ and SkQ1, metabolic modulators such as metformin and NAD⁺ boosters, mitophagy inducers like urolithin A, fission inhibitors including Mdivi-1, senolytic agents, and even mitochondrial transplantation. We conclude by proposing a precision medicine framework that matches specific mitochondrial abnormalities with mechanism-based interventions. Drawing on recent preclinical and clinical evidence, this review positions mitochondrial crosstalk as a promising foundation for developing disease-modifying therapies in musculoskeletal medicine.
