Mitochondria–endoplasmic reticulum contacts as signaling platforms in chondrocyte homeostasis and osteoarthritis: from adaptive coupling to pathological amplification

Osteoarthritis (OA) is a progressive whole-joint disease in which cartilage degeneration remains a central pathological event. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are prominent features of chondrocyte dysfunction, but how these processes are coordinated across organelles remains incompletely understood. Mitochondria–endoplasmic reticulum contacts (MERCs) are dynamic nanoscale interfaces that support Ca 2+ transfer, lipid exchange, proteostasis, mitochondrial dynamics, and organelle quality control. In chondrocytes, MERC remodeling may coordinate localized ER-to-mitochondria Ca 2+ transfer with mitochondrial metabolic support and ER proteostasis during physiological adaptation or transient stress. When mechanical or inflammatory stress persists, sustained Ca 2+ transfer and reciprocal signaling between reactive oxygen species and unfolded protein response pathways may exceed cellular compensatory capacity, thereby favoring mitochondrial permeability transition, mitochondrial damage, mitochondrial DNA release, and inflammatory or senescence-associated responses. This proposed loss of compensatory control may mark the transition from adaptive coupling to self-reinforcing pathological amplification, although direct evidence for this transition in adult articular chondrocytes is still lacking. This review summarizes the molecular organization and homeostatic functions of MERCs and evaluates their possible involvement in extracellular matrix (ECM) imbalance, Ca 2+ dysregulation, oxidative stress, senescence, inflammation, and persistent ER stress in OA. It also reviews therapeutic strategies that modulate MERC-associated pathways while distinguishing direct contact-specific evidence from findings inferred from broader mitochondrial or ER biology and from observations extrapolated from non-chondrocyte or non-articular cartilage models. Current evidence supports a MERC-centered framework as an emerging and testable model of chondrocyte dysfunction rather than a validated central driver or established therapeutic target in OA. Defining the timing, direction, and functional consequences of MERC remodeling in primary adult articular chondrocytes, cartilage explants, in vivo OA models, and human tissues will be essential for determining the causal and therapeutic relevance of this interface.