Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.

Degenerative musculoskeletal diseases (DMDs), including osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration, are highly prevalent age-related conditions characterized by progressive tissue dysfunction and loss of musculoskeletal integrity. Aging is accompanied by profound alterations in organelle homeostasis, metabolic signaling, and stress adaptation, among which mitochondria-endoplasmic reticulum communication has emerged as a critical regulatory axis. Mitochondria-associated membranes (MAMs) are specialized contact sites that spatially and functionally couple the endoplasmic reticulum and mitochondria, thereby coordinating calcium signaling, redox balance, lipid metabolism, and cell fate decisions. Accumulating evidence indicates that aging-related disruption of MAMs integrity and signaling contributes to mitochondrial dysfunction, oxidative stress, aberrant stress responses, and inflammatory activation across multiple musculoskeletal tissues. In this review, we synthesize current evidence linking MAMs-associated signaling pathways-including calcium flux, reactive oxygen species regulation, unfolded protein response signaling, autophagy, inflammasome activation, and regulated cell death-to the pathogenesis of major degenerative musculoskeletal diseases. We further highlight shared and tissue-specific mechanisms through which age-dependent MAMs dysregulation drives musculoskeletal degeneration. By framing MAMs as aging-sensitive signaling hubs, this review provides an integrated perspective on how organelle crosstalk contributes to degenerative musculoskeletal diseases and identifies conceptual frameworks for understanding disease convergence during musculoskeletal aging.