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

Apr 9, 2026Ageing research reviews

Aging-related changes in cell energy and protein-folding sites linked to muscle and bone diseases

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Abstract

Aging-related disruption of mitochondria-associated membranes (MAMs) may contribute to the dysfunction of musculoskeletal tissues.

Degenerative musculoskeletal diseases (DMDs) are characterized by tissue dysfunction and loss of musculoskeletal integrity.
Mitochondria-endoplasmic reticulum communication plays a critical role in cellular health and is altered with aging.
MAMs serve as contact sites that connect mitochondria and the endoplasmic reticulum, coordinating essential cellular processes.
Disruption of MAM integrity and signaling is linked to mitochondrial dysfunction, oxidative stress, and inflammatory activation in musculoskeletal tissues.
Age-dependent dysregulation of MAMs may drive the pathogenesis of major DMDs through various cellular signaling pathways.

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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.

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

Abstract

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