Osteoarthritis (OA) is a common age-associated joint disorder driven not only by mechanical wear but also by progressive intracellular stress, metabolic imbalance, and chronic inflammation that culminate in cartilage degeneration and functional disability. Increasing evidence identifies mitochondrial dysfunction and endoplasmic reticulum stress (ERS) as central pathological hubs regulating chondrocyte survival, extracellular matrix (ECM) integrity, and inflammatory signaling. Mitochondrial impairment promotes excessive reactive oxygen species (ROS) generation, defective ATP production, disturbed mitochondrial dynamics, and inadequate mitophagy, collectively accelerating ECM catabolism and chondrocyte apoptosis. In parallel, ERS activates the unfolded protein response (UPR) to restore proteostasis through the PERK, IRE1α, and ATF6 pathways; however, sustained UPR activation shifts from adaptive signaling to maladaptive outcomes, amplifying inflammation, oxidative injury, and cell death in OA cartilage. Notably, emerging data highlight bidirectional crosstalk between mitochondria and ER, particularly via mitochondria-associated membranes (MAMs), as a key driver of Ca²⁺ dysregulation, inflammasome activation, and degenerative joint remodeling. Therapeutic strategies targeting these stress pathways including mitochondrial antioxidants, NAD⁺-boosting agents, mitophagy modulators, chemical chaperones, and selective UPR regulators have demonstrated potential to attenuate cartilage destruction and restore joint homeostasis. This review synthesizes current mechanistic insights into mitochondrial ERS signaling in OA and critically evaluates evolving disease-modifying interventions aimed at intracellular stress reprogramming. Finally, we discuss translational challenges and future directions for developing precision therapies that exploit organelle stress pathways to improve long-term joint health.
