Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review)

Introduction

Aging is accompanied by progressive deterioration of musculoskeletal tissue homeostasis, contributing to chronic pain, impaired mobility, fragility and loss of physical independence (1–5). Osteoporosis, intervertebral disc degeneration, osteoarthritis (OA) and sarcopenia arise in distinct tissues and differ markedly in clinical presentation, yet several cellular abnormalities recur across these disorders, including disrupted Ca2+ homeostasis, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, oxidative stress, inflammatory dysregulation and altered cell fate (6–10). This convergence has focused increasing attention on communication between intracellular organelles as a component of musculoskeletal degeneration.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are specialized ER membrane domains located at sites of close apposition to mitochondria, where they coordinate Ca2+ transfer, lipid exchange, mitochondrial metabolism and quality control, and stress signaling (11,12). Studies have implicated MAM-associated molecules and ER-mitochondrial communication in osteoclast and osteoblast function, nucleus pulposus cell degeneration, chondrocyte homeostasis, and age-related skeletal muscle dysfunction (13–17). These findings place the ER-mitochondrial interface within several pathways relevant to musculoskeletal degeneration.

Current evidence is heterogeneous in both directness and biological context. Certain studies directly assessed ER-mitochondrial contact architecture or manipulated contact-site regulators (14,17,18), whereas others inferred MAM involvement from Ca2+ transfer, mitochondrial dysfunction or ER stress without measuring the interface itself (15,19–21). Contact remodeling may also differ in direction and biological consequence according to cell type, metabolic state and disease stage (15,16,22–24), and human mechanistic evidence remains limited. The pathological significance of MAM dysregulation may therefore lie less in a simple increase or decrease in ER-mitochondrial contact than in loss of context-appropriate homeostasis. The present narrative review critically compares mechanistic evidence across osteoporosis, intervertebral disc degeneration, OA/cartilage degeneration and sarcopenia/skeletal muscle atrophy, with emphasis on the directness of evidence, cross-disease differences, unresolved questions and therapeutic implications.

Literature search

Literature searches were conducted in PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Web of Science (https://www.webofscience.com/) from database inception through to August 15, 2026. Search terms combined ‘mitochondria-associated endoplasmic reticulum membrane(s)’, ‘MAM(s)’, ‘ER-mitochondrial contact(s)’ and ‘MERC(s)’ with ‘osteoporosis’, ‘intervertebral disc degeneration’, ‘osteoarthritis’, ‘sarcopenia’ and ‘skeletal muscle atrophy’. Peer-reviewed studies examining MAM structure, MAM-associated molecules or ER-mitochondrial communication in relevant cellular, animal or human tissue models were prioritized. Studies outside the musculoskeletal scope, duplicate reports and articles with only peripheral relevance to ER-mitochondrial communication were excluded. Reference lists of key articles were also screened for additional relevant studies.

MAM biology in disease

Core structural and functional features relevant to disease interpretation

MAMs are dynamic ER membrane domains located at sites of close apposition to mitochondria. Their extent, spacing and molecular composition vary across cell types and physiological states (25–30). ER-mitochondrial contacts are organized by multiple tethering and regulatory systems, including mitofusin 2 (MFN2), vesicle-associated membrane protein-associated protein B-protein tyrosine phosphatase-interacting protein 51, mitochondrial fission 1 protein-B-cell receptor-associated protein 31 and PDZ domain-containing protein 8 (31–37), while the inositol 1,4,5-trisphosphate receptor (IP3R)-glucose-regulated protein 75 (GRP75)-voltage-dependent anion channel 1 (VDAC1) complex provides a major route for Ca2+ transfer from the ER to mitochondria (38,39).

Ca2+ transfer at these interfaces couples intracellular signaling to mitochondrial metabolism and stress responses (19,38,39). Excessive transfer can produce mitochondrial Ca2+ overload, oxidative stress, loss of membrane potential and cell injury (19,40). MAMs also support non-vesicular phospholipid exchange between the two organelles. Phosphatidylserine synthesized in the ER is transferred to mitochondria for conversion to phosphatidylethanolamine, while oxysterol-binding protein-related proteins 5 and 8 and extended synaptotagmin 1 participate in lipid transfer and the maintenance of mitochondrial membrane composition and respiration (41–45). Direct evidence linking this lipid-transfer machinery to musculoskeletal degeneration remains sparse. The major structural and signaling modules of MAMs are summarized in Fig. 1.

Figure 1. Molecular organization of MAMs. MAMs are specialized ER domains closely apposed to mitochondria that coordinate inter-organelle communication. The enlarged interface illustrates representative tethering and regulatory modules, including VAPB-PTPIP51 and PDZD8-FKBP8, the IP3R-GRP75-VDAC1-MCU Ca2+ transfer axis, MFN2-mediated contact regulation, and MAM-associated Sig-1R and BAP31-Fis1 signaling. Solid lines denote direct tethering interactions, dashed lines denote contact regulation and dotted lines denote regulatory or signaling associations. BAP31, B-cell receptor-associated protein 31; ER, endoplasmic reticulum; Fis1, mitochondrial fission 1 protein; FKBP8, FK506-binding protein 8; GRP75, glucose-regulated protein 75; IMM, inner mitochondrial membrane; IP3R, inositol 1,4,5-trisphosphate receptor; MAMs, mitochondria-associated endoplasmic reticulum membranes; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; OMM, outer mitochondrial membrane; PDZD8, PDZ domain-containing protein 8; PTPIP51, protein tyrosine phosphatase-interacting protein 51; Sig-1R, sigma-1 receptor; VAPB, vesicle-associated membrane protein-associated protein B; VDAC1, voltage-dependent anion channel 1.

ER-mitochondrial contacts also participate in mitochondrial fission, mitophagy and stress signaling. Dynamin-related protein 1 (DRP1), phosphofurin acidic cluster sorting protein 2 (PACS-2)/receptor accessory protein 5 and FUN14 domain-containing protein 1 link contact-site organization to mitochondrial dynamics and quality control (46–50), whereas Sigma-1 receptor (Sig-1R), inositol-requiring enzyme 1α (IRE1α)/mitochondrial ubiquitin ligase and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/MFN2 connect the interface to ER stress responses (51–53). Autophagosome formation can initiate at ER-mitochondrial contacts, and disturbances at these sites have also been linked to apoptosis and ferroptosis (54–56).

ER-mitochondrial stress is also coupled to inflammasome activation. During NLR family pyrin domain containing 3 (NLRP3) activation, NLRP3 and the adaptor apoptosis-associated speck-like protein containing a CARD redistribute toward ER-mitochondrial regions, while mitochondrial reactive oxygen species (ROS) and Ca2+ signaling contribute to inflammasome assembly and activation (57,58). Direct evidence linking MAMs to NLRP3 activation in degenerative musculoskeletal tissues remains limited. The core MAM-associated modules relevant to musculoskeletal degeneration are summarized in Table I (59–62).

Table I. Core structural and functional modules of MAMs relevant to musculoskeletal degeneration.

Table I.

Core structural and functional modules of MAMs relevant to musculoskeletal degeneration.

Core MAM-associated module	Representative molecules/complexes	Principal function at the ER-mitochondrial interface	Relevance to musculoskeletal degeneration	(Refs.)
Contact organization and tethering	MFN2; VAPB-PTPIP51; PDZD8; Fis1-BAP31	Maintain ER-mitochondrial proximity and organize contact-site architecture	Altered contact organization can disrupt inter-organelle signaling and stress adaptation	(31–37)
Ca2+ transfer and metabolic coupling	IP3R-GRP75-VDAC1; MCU; SERCA	Couple ER Ca2+ release to mitochondrial uptake and metabolic responses	Dysregulated Ca2+ transfer contributes to mitochondrial Ca2+ overload, oxidative stress and cell injury	(19,38-40,59-62)
Lipid transfer and metabolic coordination	PSS/PSD; ORP5/8; E-Syt1	Mediate phospholipid exchange and support mitochondrial membrane composition and respiration	Direct evidence linking this machinery to musculoskeletal degeneration remains sparse	(41–45)
Mitochondrial dynamics and quality control	DRP1; PACS-2/REEP5; FUNDC1	Coordinate mitochondrial fission, distribution, mitophagy and contact-site remodeling	Disturbance of these processes is associated with mitochondrial fragmentation, impaired quality control and reduced stress tolerance	(46–50)
Stress, cell-fate and inflammatory signaling	Sig-1R; IRE1α/MITOL; PERK/MFN2; NLRP3/ASC (activation-associated recruitment)	Integrate ER stress with autophagy, apoptosis, ferroptosis and inflammasome signaling	Connect ER-mitochondrial stress with degenerative cell responses and inflammatory signaling	(51–58)

[i] ASC, apoptosis-associated speck-like protein containing a CARD; BAP31, B-cell receptor-associated protein 31; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; E-Syt1, extended synaptotagmin 1; Fis1, mitochondrial fission 1 protein; FUNDC1, FUN14 domain-containing protein 1; GRP75, glucose-regulated protein 75; IP3R, inositol 1,4,5-trisphosphate receptor; IRE1α, inositol-requiring enzyme 1α; MAMs, mitochondria-associated endoplasmic reticulum membranes; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; MITOL, mitochondrial ubiquitin ligase; NLRP3, NLR family pyrin domain containing 3; ORP5/8, oxysterol-binding protein-related proteins 5 and 8; PACS-2, phosphofurin acidic cluster sorting protein 2; PDZD8, PDZ domain-containing protein 8; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PSD, phosphatidylserine decarboxylase; PSS, phosphatidylserine synthase; PTPIP51, protein tyrosine phosphatase-interacting protein 51; REEP5, receptor accessory protein 5; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; Sig-1R, sigma-1 receptor; VAPB, vesicle-associated membrane protein-associated protein B; VDAC1, voltage-dependent anion channel 1.

Direct MAM evidence vs. MAM-related functional inference

Evidence for MAM involvement varies depending on how directly ER-mitochondrial contacts are examined. Structural or biochemical assessment of contact sites by ultrastructural imaging, MAM fractionation or contact-site proteomics provides the most direct evidence, particularly when combined with perturbation of tethering or contact-site regulators and corresponding phenotypic changes (13,14,18,25,63). Studies of MAM-resident or tethering proteins also provide mechanistic evidence, but changes in these proteins do not establish contact-site remodeling unless MAM architecture is measured. Other studies infer MAM involvement from ER-to-mitochondrial Ca2+ transfer, mitochondrial Ca2+ overload, ER stress or mitochondrial dysfunction (15,19–21). These processes are closely linked to the ER-mitochondrial interface but are not specific measures of MAM structure.

Disease-specific causal evidence is most developed in intervertebral disc degeneration (IVDD), where disrupted MAM integrity and phenotypic rescue have been linked to synaptojanin 2 binding protein (SYNJ2BP) and PACS-2 (14,18). In osteoporosis, the strongest data concern MFN2- and Sig-1R-dependent regulation of osteoclast function, with additional evidence from osteoblast and vascular models (15,64–67). OA studies now include direct assessment of abnormal ER-mitochondrial contacts (17,68), although the number of mechanistic studies remains small. Aging skeletal muscle has been examined using ultrastructural and proteomic approaches (13,69,70); evidence specific to clinical sarcopenia, however, still largely comes from aging, hereditary myopathy and metabolic models (21–24,71–74).

Role of MAMs in degenerative musculoskeletal disorders

Osteoporosis

Osteoporosis is a systemic skeletal disorder characterized by low bone mass and deterioration of bone microarchitecture, resulting in increased bone fragility and fracture risk (8). Current MAM-related evidence is concentrated in osteoclast biology, with additional findings from osteoblast-lineage cells and the bone vascular microenvironment.

Jung et al (15) showed that MFN2 promotes receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation through the Ca2+-calcineurin-nuclear factor of activated T cells 1 (NFATc1) axis. Ballard et al (65) further showed that its tethering function is required for this effect: Mfn2 deficiency impaired store-operated Ca2+ entry, reduced NFATc1 activation and increased bone mass. Wei et al (64) identified a related mechanism involving the MAM-localized Sig-1R, which suppresses osteoclastogenesis by promoting ER-associated degradation of sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2); deficiency of the gene encoding Sig-1R (Sigmar1) aggravated bone loss in ovariectomized mice. PTEN-induced kinase 1 (PINK1) has also been linked to MAM-dependent Ca2+ signaling in osteoclasts, although these data were obtained in periodontitis-associated bone loss rather than osteoporosis (75).

In osteolineage cells, Mfn2 deletion produced a different skeletal phenotype. Osteolineage-specific Mfn2 depletion increased cortical bone formation in female mice and enhanced oxygen consumption and mineralization during early osteogenic differentiation (16). The contrasting effects of MFN2 in osteoclasts and osteolineage cells argue against a uniform skeletal role across bone-cell compartments. In diabetic osteopenia, BK channel activation preserved osteoblast function and reduced bone loss through regulation of mitochondrial Ca2+ and solute carrier family 25 member 5/adenine nucleotide translocator 2-PINK1-parkin RBR E3 ubiquitin protein ligase-mediated mitophagy (66). ER-mitochondrial contact remodeling, however, was not directly examined in this study.

MAM-associated regulation also extends to the bone vascular compartment. Wang et al (67) reported that eldecalcitol (ED-71) preserved mitochondrial Ca2+ homeostasis in type H vascular endothelial cells, reduced glucocorticoid-induced senescence and improved angiogenesis-osteogenesis coupling. Mechanistic support in osteoporosis is currently strongest in osteoclasts. Direct structural evidence of MAM remodeling remains sparse and several supporting studies derive from periodontitis-, diabetes- or glucocorticoid-associated bone-loss models.

IVDD

IVDD is characterized by progressive loss of nucleus pulposus cell homeostasis, extracellular matrix breakdown, cellular senescence and cell death. Evidence for MAM involvement includes both altered ER-mitochondrial ion transfer and direct changes in contact-site integrity.

In nucleus pulposus cells exposed to excessive mechanical compression, Lin et al (20) found increased ER stress and ER-mitochondrial Ca2+ transfer. Inhibition of ER stress or blockade of the IP3R-GRP75-VDAC1 axis reduced mitochondrial Ca2+ overload and poly(ADP-ribose) polymerase-apoptosis-inducing factor-associated programmed necrosis. Zheng et al (76) showed that site-1 protease deficiency caused ER distension and increased ER-mitochondrial contacts, while disrupting ER-to-mitochondrial Ca2+ transfer and accelerating nucleus pulposus cell senescence and disc degeneration.

Song et al (14) observed disrupted MAM integrity in degenerative disc tissue and tert-butyl hydroperoxide-treated nucleus pulposus cells. SYNJ2BP deficiency was associated with mitochondrial Zn2+ overload and cellular senescence, whereas SYNJ2BP overexpression promoted MAM formation, stabilized the NLR family member X1 (NLRX1)-solute carrier family 39 member 7 (SLC39A7) complex, restored mitochondrial Zn2+ homeostasis and attenuated disc degeneration.

Kang et al (18) reported impaired MAM integrity and reduced PACS-2 expression in degenerative human and rat disc tissues and in nucleus pulposus-derived stem cells exposed to an acidic microenvironment. PACS-2 preserved ER-mitochondrial contacts through the specificity protein 1 (SP1)/leucine-rich repeat kinase 2 (LRRK2)/MFN2 axis, reduced ER stress and mitochondrial dysfunction and limited stem-cell apoptosis. Loss of PACS-2 aggravated disc degeneration, whereas its restoration improved the reparative effect of transplanted cells. Human degenerative disc tissues support the presence of MAM disruption, while causal rescue has so far been demonstrated mainly in experimental models.

OA/cartilage degeneration

OA is characterized by progressive articular cartilage degeneration and impaired chondrocyte homeostasis. Studies in OA have identified MAM-related transcriptional signatures and experimentally linked ER-mitochondrial communication to chondrocyte dysfunction (17,68,77,78).

Li et al (77) identified MAM-related genes associated with OA and cellular senescence, including protein tyrosine phosphatase non-receptor type 1 and inositol 1,4,5-trisphosphate receptor type 1. ER-mitochondrial contacts were not directly assessed in this study. Hou et al (17) showed that loss of MFN2 impaired mitochondrial function and cartilage matrix metabolism, with fewer mitochondrial-ER junctions also observed in damaged human cartilage. Sirtuin 3 stabilized MFN2, while MFN2-mediated mitochondrial-ER junctions supported Ca2+ homeostasis and reduced chondrocyte senescence. Intra-articular delivery of MFN2 mRNA attenuated cartilage degeneration in experimental OA models.

ER-mitochondrial Ca2+ transfer has also been linked to chondrocyte apoptosis. In temporomandibular joint OA, optineurin deficiency enhanced Ca2+ transfer through the IP3R-GRP75-VDAC1 complex, increased mitochondrial Ca2+ loading and promoted apoptosis (78). Pharmacological inhibition of this pathway reduced Ca2+ overload and apoptosis.

Song et al (68) showed that inflammatory stress increased aberrant ER-mitochondrial contacts in chondrocytes. Circular RNA ZFP609 (cZFP609) stabilized oligomeric binding immunoglobulin protein (BiP), attenuated IRE1α-associated ER stress, reduced aberrant ER-mitochondrial contacts and suppressed lipid peroxidation and ferroptosis. Intra-articular cZFP609 delivery also reduced cartilage degeneration in an experimental OA model. Human cartilage provides structural evidence of altered ER-mitochondrial contacts, whereas causal rescue and therapeutic testing remain predominantly preclinical.

Sarcopenia/skeletal muscle atrophy

Sarcopenia is an age-related skeletal muscle disorder characterized by progressive loss of muscle mass and function. Most structural evidence concerning the ER-mitochondrial interface comes from aging skeletal muscle rather than clinically defined sarcopenia.

Lu et al (13) identified age-related changes in MAM ultrastructure and protein composition in striated muscle using electron microscopy and proteomic profiling. Allen et al (69) likewise detected early alterations in ER-mitochondrial contacts and MAM protein composition in aging skeletal muscle, changes that were prevented by exercise. Unten et al (70) reported increased mitochondria-ER contact sites (MERCs) in myoblasts from older human donors. MERCs denote the physical contacts between the two organelles, whereas MAMs more specifically refer to the membrane domains and molecular components associated with these interfaces.

Ca2+ transfer at these contacts has also been linked to age-related muscle atrophy. Shi et al (21) showed that age-related reduction of thyroid hormone receptor α increased IP3R type 1-mediated Ca2+ transfer and MAM formation, leading to mitochondrial Ca2+ overload, mitochondrial dysfunction and skeletal muscle atrophy in mice. Separately, Grepper et al (71) localized BCL2-like 13 to ER-mitochondrial contact sites and showed that its loss altered Ca2+ dynamics and impaired skeletal muscle function, without changing the contact-site number.

Additional mechanisms have been identified in hereditary and metabolic muscle models. Selenoprotein N-related myopathy is associated with defective ER-mitochondrial contacts and impaired bioenergetics (72), whereas OPA1 mitochondrial dynamin-like GTPase deficiency increases ER-mitochondrial tethering through an activating transcription factor 4-dependent response (22). Metabolic studies have reported both reduced ER-mitochondrial coupling and excessive MAM formation in insulin-resistant skeletal muscle (23,24,74). Clinical validation in well-characterized sarcopenia populations remains limited.

Cross-disease synthesis

Recurrent abnormalities in Ca2+ signaling, mitochondrial function and ER stress occur across the disorders discussed above, but they do not imply a uniform MAM defect. ER-to-mitochondrial Ca2+ transfer has been directly interrogated in several disease models (20,21,78), whereas mitochondrial dysfunction or ER stress alone cannot establish altered contact-site organization. The common molecular pattern therefore reflects convergence on organelle stress pathways more clearly than a uniform structural defect at the ER-mitochondrial interface.

The direction of MAM remodeling also varies by cellular context. MFN2 promotes osteoclast differentiation through Ca2+-dependent signaling, whereas osteolineage-specific Mfn2 depletion enhances cortical bone formation (15,16,65). In skeletal muscle, both loss of contact integrity and stress-associated increases in ER-mitochondrial tethering have been reported (13,22–24), while endurance exercise can reduce ER-mitochondrial contacts (79). Contact abundance alone is therefore an inadequate marker of dysfunction. These observations point to cell type, metabolic state and disease stage as key determinants of whether contact remodeling is adaptive or maladaptive.

Translational evidence remains uneven across disorders. Direct structural and causal evidence is concentrated in IVDD and selected OA models, whereas osteoporosis and skeletal muscle studies rely more heavily on molecular or functional readouts and preclinical systems. Human interventional validation remains limited, particularly in clinically defined sarcopenia.

Taken together, these observations support a disease-oriented framework in which distinct MAM-associated processes converge on disrupted MAM homeostasis and shared downstream consequences, while giving rise to tissue-specific outcomes across osteoporosis, intervertebral disc degeneration, OA and sarcopenia/skeletal muscle atrophy (Fig. 2). A comparative summary of disease-specific evidence strength, directness and translational status is provided in Table II.

Figure 2. Disease-oriented framework of MAM dysregulation in degenerative musculoskeletal disorders. Major disease-relevant MAM processes, including contact organization and tethering, Ca2+ transfer and bioenergetic coupling, mitochondrial dynamics and quality control, and ER stress/cell-fate signaling, converge on disrupted MAM homeostasis. Shared downstream consequences include Ca2+ dyshomeostasis, mitochondrial dysfunction, impaired quality control, ER and oxidative stress, metabolic dysfunction and senescence- or cell death-related signaling. These alterations are linked to representative disease outcomes in osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy. The consequences of MAM dysregulation are context-dependent and vary with cell type, metabolic state, and disease stage. ER, endoplasmic reticulum; IVDD, intervertebral disc degeneration; MAM, mitochondria-associated endoplasmic reticulum membrane.

Table II. Comparative evidence for MAM involvement in degenerative musculoskeletal disorders.

Table II.

Comparative evidence for MAM involvement in degenerative musculoskeletal disorders.

Disorder	Principal cells/tissues	Representative MAM-related molecules/pathways	Contact-site/structural evidence	Functional/mechanistic evidence	Human evidence/translational status	(Refs.)
Osteoporosis	Osteoclasts; osteoblast-lineage cells; type H vascular endothelial cells	MFN2; Sig-1R/ SERCA2; PINK1; SLC25A5/ANT2- PINK1- PRKN	Direct structural assessment of MAM remodeling remains limited; most studies examine MAM- associated proteins or Ca2+- related functions	MFN2-dependent Ca2+-NFATc1 signaling regulates osteoclastogenesis; Sig-1R suppresses osteoclast differentiation; MAM-related Ca2+ and mitochondrial quality-control pathways have also been implicated in osteoblast and vascular models	Evidence remains predominantly preclinical and includes ovariectomy-, periodontitis-, diabetes- and glucocorticoid- associated bone- loss models; direct human validation is limited	(15,16,64-67,75)
Intervertebral disc degeneration	Nucleus pulposus cells; nucleus pulposus-derived stem cells	SYNJ2BP; PACS- 2; S1P; IP3R- GRP75-VDAC1; NLRX1- SLC39A7; SP1/ LRRK2/MFN2	Altered MAM integrity has been demonstrated in degenerative disc tissues and experimental models; SYNJ2BP and PACS-2 manipulation modifies contact-site integrity	Abnormal ER- mitochondrial Ca2+/Zn2+ handling is linked to ER stress, mitochondrial dysfunction, senescence and apoptosis	Human degenerative disc tissues show MAM abnormalities; causal rescue and therapeutic testing remain mainly preclinical	(14,18,20,76)
Osteoarthritis/cartilage degeneration	Articular chondrocytes; human cartilage; temporomandibular joint chondrocytes	MFN2/SIRT3; OPTN; IP3R- GRP75-VDAC1; cZFP609/BiP- IRE1α; PTPN1; ITPR1	Altered mitochondrial- ER junctions have been observed in damaged human cartilage and experimental OA; inflammatory stress can induce aberrant ER- mitochondrial contacts	MFN2-dependent contact regulation affects chondrocyte homeostasis; abnormal Ca2+ transfer promotes apoptosis; cZFP609 regulates ER stress, ferroptosis and contact remodeling	Human cartilage provides structural evidence; causal rescue and therapeutic intervention remain predominantly preclinical	(17,68,77,78)
Sarcopenia/skeletal muscle atrophy	Skeletal muscle fibers; myoblasts	TRα/IP3R1; BCL2L13; OPA1/ATF4	Aging skeletal muscle shows ultrastructural and proteomic remodeling of MAMs/MERCs; altered contacts have also been observed in aged human myoblasts	Age-related MAM Ca2+ transfer contributes to mitochondrial Ca2+ overload and muscle atrophy; hereditary and metabolic models show both reduced and excessive ER- mitochondrial coupling	Human evidence derives mainly from aging skeletal muscle and myoblast studies; mechanistic evidence specific to clinically defined sarcopenia remains limited	(13,21-24,69-74)

[i] Evidence strength and directness differ across musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM-associated regulators and functional pathways, whereas sarcopenia-specific evidence remains largely derived from aging skeletal muscle and related experimental models. Recurrent pathological axes across these conditions include Ca²⁺ dyshomeostasis, mitochondrial dysfunction, endoplasmic reticulum stress and altered cell-fate regulation. ATF4, activating transcription factor 4; BCL2L13, BCL2-like 13; BiP, binding immunoglobulin protein; cZFP609, circular RNA ZFP609; ER, endoplasmic reticulum; GRP75, glucose-regulated protein 75; IP3R, inositol 1,4,5-trisphosphate receptor; IRE1α, inositol-requiring enzyme 1α; ITPR1, inositol 1,4,5-trisphosphate receptor type 1; IVDD, intervertebral disc degeneration; LRRK2, leucine-rich repeat kinase 2; MAM(s), mitochondria-associated endoplasmic reticulum membrane(s); MERCs, mitochondria-endoplasmic reticulum contact sites; MFN2, mitofusin 2; NFATc1, nuclear factor of activated T cells 1; NLRX1, NLR family member X1; OA, osteoarthritis; OPA1, OPA1 mitochondrial dynamin-like GTPase; OPTN, optineurin; PACS-2, phosphofurin acidic cluster sorting protein 2; PINK1, PTEN-induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; PTPN1, protein tyrosine phosphatase non-receptor type 1; S1P, site-1 protease; SERCA2, sarco/endoplasmic reticulum Ca²⁺-ATPase 2; Sig-1R, sigma-1 receptor; SIRT3, sirtuin 3; SLC25A5/ANT2, solute carrier family 25 member 5/adenine nucleotide translocator 2; SLC39A7, solute carrier family 39 member 7; SP1, specificity protein 1; SYNJ2BP, synaptojanin 2 binding protein; TRα, thyroid hormone receptor α; VDAC1, voltage-dependent anion channel 1.

Therapeutic perspectives

Modulation of MAM structure and contact-site regulators

MAM organization can be modified through contact-site regulators, membrane composition and MAM-resident proteins. Genetic restoration of contact-site regulators has been examined in IVDD models. SYNJ2BP overexpression promoted MAM formation and NLRX1-SLC39A7 complex assembly, restored mitochondrial Zn2+ homeostasis and reduced nucleus pulposus cell senescence and disc degeneration (14). PACS-2 restoration similarly preserved MAM integrity through the SP1/LRRK2/MFN2 pathway, reduced apoptosis of nucleus pulposus-derived stem cells and improved the reparative efficacy of transplanted cells (18).

Contact organization can also be altered without directly manipulating classical tethering proteins. In OA models, cZFP609 stabilized oligomeric BiP, attenuated IRE1α-associated ER stress, reduced aberrant ER-mitochondrial contacts, and suppressed chondrocyte ferroptosis and cartilage degeneration (68). In palmitic acid-exposed nucleus pulposus cells, phosphatidylcholine increased ER-mitochondrial interactions, restored mitochondrial phosphatidylcholine content and fatty-acid oxidation and alleviated lipotoxic injury (80).

Pharmacological modulation of a MAM-resident protein has been demonstrated in experimental bone-loss models. Sig-1R activation suppressed osteoclastogenesis by promoting ER-associated degradation of SERCA2, whereas Sigmar1 deficiency aggravated bone loss (64). Local Sigmar1 overexpression and treatment with the Sig-1R agonist dimemorfan preserved bone mass in experimental models.

Pharmacological modulation of MAM-related functions

Beyond direct manipulation of contact-site organization, pharmacological studies have largely targeted functional processes coordinated at the ER-mitochondrial interface, particularly Ca2+ handling and mitochondrial homeostasis. Ruthenium Red suppressed RANKL-induced ROS production and NFATc1 activation, inhibited osteoclastogenesis and reduced bone loss in ovariectomized mice (81). Mitochondria-targeted Ca2+-regulating nanoparticles reduced mitochondrial Ca2+ overload and pro-inflammatory macrophage polarization in experimental OA (82). In glucocorticoid-induced bone loss, ED-71 reduced GRP75-dependent MAM-mediated mitochondrial Ca2+ overload in type H vascular endothelial cells and attenuated cellular senescence (67).

Proteins controlling Ca2+ transfer and mitochondrial permeability have also been targeted in dystrophin-deficient muscle. MKT077 inhibited GRP75-dependent Ca2+ transfer from the sarcoplasmic reticulum to mitochondria, reduced mitochondrial Ca2+ overload and alleviated muscle pathology in mdx mice (83). Alisporivir improved mitochondrial Ca2+ handling and mitochondrial homeostasis in dystrophin-deficient muscle (84), while VBIT-4, a voltage-dependent anion channel inhibitor, reduced mitochondrial Ca2+ overload and partially improved muscle pathology in a severe Duchenne muscular dystrophy model (85). The relevance of these findings to sarcopenia remains indirect because the evidence derives from dystrophin-deficient muscle models.

Pharmacological evidence for MAM-linked ER stress signaling is less developed in degenerative musculoskeletal disease. PERK and IRE1α signaling pathways are closely associated with ER-mitochondrial stress communication, but most musculoskeletal studies have examined ER stress without directly assessing changes in MAM organization (86–88).

Physiological and systemic modulation of ER-mitochondrial communication

Beyond molecular and pharmacological interventions, ER-mitochondrial communication is also responsive to physiological and metabolic cues. Exercise provides the clearest example in skeletal muscle. Endurance exercise alters ER-mitochondrial contacts in a demand-dependent manner (79), and exercise prevented early age-related abnormalities in these contacts in aging muscle (69). In diabetic skeletal muscle, swimming also modified MAM-related ER stress and mitochondrial dysfunction (73). Exercise-related changes in ER-mitochondrial contacts therefore appear to form part of the broader metabolic adaptation of skeletal muscle.

Metabolic state itself can reshape the ER-mitochondrial interface. Reduced MAM integrity has been associated with skeletal muscle insulin resistance (23), whereas obesity-related activation of pyruvate dehydrogenase kinase 4 can increase ER-mitochondrial contact and impair insulin signaling (24). Muscle-specific p53 deletion likewise modifies MAM organization in diet-induced insulin resistance (74). A smaller number of bioactive interventions have been linked more directly to MAM-related functions. Polygonatum sibiricum polysaccharide improved skeletal muscle aging phenotypes by regulating MAM-mediated Ca2+ homeostasis (89). Representative experimental interventions targeting MAM structure or MAM-related functions are summarized in Table III.

Table III. Representative experimental interventions targeting MAM structure or MAM-related functions relevant to degenerative musculoskeletal disorders.

Table III.

Representative experimental interventions targeting MAM structure or MAM-related functions relevant to degenerative musculoskeletal disorders.

Intervention	MAM-related target or mechanism	Disease/model	Main reported effect	Evidence level and MAM directness	(Refs.)
SYNJ2BP overexpression	SYNJ2BP-dependent MAM formation; NLRX1-SLC39A7 complex; mitochondrial Zn2+ homeostasis	IVDD; nucleus pulposus cells and experimental disc degeneration	Restored MAM formation and mitochondrial Zn2+ homeostasis; reduced cellular senescence and disc degeneration	Cell + animal; direct contact-site evidence	(14)
PACS-2 overexpression	PACS-2-SP1/ LRRK2/MFN2 axis; MAM integrity	IVDD; degenerative disc tissues, nucleus pulposus-derived stem cells and experimental IVDD	Preserved MAM integrity; reduced ER stress, mitochondrial dysfunction and apoptosis; improved reparative efficacy	Human tissue association + cell/animal intervention; direct contact-site evidence	(18)
cZFP609 delivery	BiP-IRE1α signaling; aberrant ER-mitochondrial contacts	OA; chondrocytes and experimental OA	Reduced aberrant contacts, ER stress, lipid peroxidation and ferroptosis; attenuated cartilage degeneration	Cell + animal; direct contact-site evidence	(68)
Phosphatidylcholine	ER-mitochondrial contact formation; mitochondrial phosphatidylcholine content and fatty-acid oxidation	IVDD; palmitic acid- exposed nucleus pulposus cells	Increased ER-mitochondrial interactions, restored mitochondrial lipid metabolism and reduced lipotoxic injury	Cell; direct contact modulation	(80)
Dimemorfan (Sig-1R agonist)	MAM-resident Sig- 1R; SERCA2 degradation	Osteoclasts and experimental bone-loss models	Suppressed osteoclastogenesis and preserved bone mass	Cell + animal; MAM-resident target evidence	(64)
Ruthenium Red	Mitochondrial Ca2+ uptake/MCU- associated pathway	Osteoclasts and ovariectomized mice	Reduced mitochondrial Ca2+ uptake, ROS production and NFATc1 activation; inhibited osteoclastogenesis and bone loss	Cell + animal; MAM-related functional evidence	(81)
Mitochondrial Ca2+ nanoregulators	Mitochondrial Ca2+ homeostasis	OA; macrophages and experimental OA	Reduced mitochondrial Ca2+ dysregulation and pro- inflammatory macrophage polarization; attenuated OA pathology	Cell + animal; MAM-related functional evidence	(82)
Eldecalcitol (ED-71)	GRP75-dependent MAM-mediated mitochondrial Ca2+ homeostasis	Glucocorticoid- induced bone loss; type H vascular endothelial cells	Reduced mitochondrial Ca2+ overload and endothelial senescence; preserved angiogenesis-osteogenesis coupling	Cell + animal; MAM-associated functional evidence	(67)
MKT077	GRP75-dependent ER/SR-to- mitochondrial Ca2+ transfer	Dystrophin- deficient mdx mice	Reduced mitochondrial Ca2+ overload and skeletal muscle pathology	Animal; contact- associated functional evidence; indirect to sarcopenia	(83)
Alisporivir	Mitochondrial Ca2+ handling and mitophagy	Dystrophin- deficient mice	Improved mitochondrial Ca2+ handling and mitophagy and reduced muscle pathology	Animal; MAM- related functional evidence; indirect to sarcopenia	(84)
VBIT-4	VDAC-dependent mitochondrial Ca2+ handling	Severe Duchenne muscular dystrophy model	Reduced mitochondrial Ca2+ overload and mitochondrial dysfunction; partially attenuated muscle pathology	Animal; MAM- related functional evidence; indirect to sarcopenia	(85)
Polygonatum sibiricum polysaccharide	MAM-mediated Ca2+ homeostasis	Aging C2C12 and myotubes and aged mice	Modulated MAM formation Ca2+ homeostasis; improved age-related skeletal muscle phenotypes	Cell + animal; MAM- related functional evidence in aging muscle	(89)

[i] Evidence level indicates the experimental system in which the intervention was evaluated, whereas MAM directness distinguishes direct assessment or manipulation of ER-mitochondrial contacts from interventions acting on MAM-associated molecules or functions. These categories describe the nature of the available evidence and do not constitute a formal methodological quality grading system. BiP, binding immunoglobulin protein; cZFP609, circular RNA ZFP609; ED-71, eldecalcitol; ER, endoplasmic reticulum; GRP75, glucose-regulated protein 75; IRE1α, inositol-requiring enzyme 1α; IVDD, intervertebral disc degeneration; LRRK2, leucine-rich repeat kinase 2; MAM, mitochondria-associated endoplasmic reticulum membrane; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; NFATc1, nuclear factor of activated T cells 1; NLRX1, NLR family member X1; OA, osteoarthritis; PACS-2, phosphofurin acidic cluster sorting protein 2; ROS, reactive oxygen species; SERCA2, sarco/endoplasmic reticulum Ca²⁺-ATPase 2; Sig-1R, sigma-1 receptor; SLC39A7, solute carrier family 39 member 7; SP1, specificity protein 1; SR, sarcoplasmic reticulum; SYNJ2BP, synaptojanin 2 binding protein; VDAC, voltage-dependent anion channel.

Translational barriers, unresolved issues and future directions

A major barrier to the field is the lack of a standardized approach for defining MAM remodeling. Transmission electron microscopy and electron tomography provide ultrastructural information on contact distance, extent and three-dimensional organization, whereas proximity ligation assays assess molecular proximity and genetically encoded contact reporters enable dynamic monitoring of ER-mitochondrial interactions. MAM fractionation characterizes the biochemical composition of contact-site fractions, while live-cell Ca2+ imaging measures functional ER-to-mitochondrial signaling. These approaches interrogate different features of the interface and are not interchangeable. Changes in contact distance, abundance of a MAM-associated protein or Ca2+ transfer alone cannot define the structural and functional state of the contact site. Combining structural and functional measurements within the same experimental system would improve comparison across tissues, models and disease stages (25,63,90).

Molecular profiling can add disease- and cell-specific context to these measurements. MAM-enriched and proximity-labeling proteomics can resolve changes in contact-site composition, whereas single-cell and spatial transcriptomic approaches can localize MAM-associated pathways to defined cell populations and tissue regions. Public transcriptomic datasets from aging and diseased skeletal muscle may also help prioritize candidate regulators and examine their associations with age, disease severity or treatment response. Because transcriptomic signatures do not demonstrate physical ER-mitochondrial contacts, candidates identified through these datasets require structural or functional validation (13,63,77,90).

Human validation remains limited. Most causal studies rely on cultured cells and animal models, whereas human evidence is derived largely from cross-sectional tissue analyses (14,18,23,70). Well-phenotyped patient-derived tissues and primary cells, together with stage-stratified and, where feasible, longitudinal sampling, could help determine whether MAM alterations precede tissue degeneration or arise during disease progression. Integration with clinically relevant phenotypes will also be necessary to establish the disease relevance of contact-site abnormalities across bone, cartilage, intervertebral disc and skeletal muscle.

Therapeutic translation is further constrained by target specificity. Many interventions discussed above modify Ca2+ handling, mitochondrial permeability, ER stress or systemic metabolism without acting selectively at MAMs (67,81–85,89). Preclinical studies therefore need to demonstrate target engagement at the ER-mitochondrial interface rather than infer MAM correction solely from downstream mitochondrial or stress responses. Candidate interventions should link contact-site modulation to disease-relevant functional outcomes and ultimately be validated in human tissues or patient-derived systems.

Conclusions

Current evidence implicates MAMs in musculoskeletal degeneration, but the strength and directness of this evidence vary substantially across diseases and experimental settings. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected OA models, whereas evidence in osteoporosis derives mainly from MAM-associated regulators and functional pathways, and sarcopenia-specific mechanisms remain largely informed by aging muscle and related experimental models. These differences argue against a uniform MAM defect across musculoskeletal disorders and indicate that the consequences of ER-mitochondrial contact remodeling depend on cell type, metabolic state and disease stage. Therapeutic modulation of contact-site regulators, Ca2+ handling and mitochondrial homeostasis has shown preclinical effects, but MAM-specific target engagement and human validation remain limited. Determining whether MAM modulation can be translated into disease-modifying strategies will require integrated structural and functional assessment, standardized contact-site measurements, and validation in clinically characterized human tissues and patient-derived systems.

Acknowledgements

Not applicable.

Funding

This study was supported by the National Natural Science Foundation of China (grant no. 82274272) and the Zhejiang Chinese Medical University Institutional Key Research Support Program (grant no. 2025JKZDZC10). The funders had no role in the design of the review, analysis or interpretation of the literature or writing of the manuscript.

Availability of data and materials

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Authors' contributions

SLM, XLF and YWX drafted the manuscript. YGC, YWX and BBT conceived and designed the review. XZ and ZLP performed the literature search, information extraction and organization of the relevant data, and contributed to reviewing and revising the manuscript KL and XLS critically revised the manuscript and supervised the preparation of the review, providing overall quality control. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Use of artificial intelligence tools

During the preparation of this work, AI tools were used to improve the readability and language of the manuscript, and subsequently, the authors revised and edited the content produced by the AI tools as necessary, taking full responsibility for the ultimate content of the present manuscript.

Glossary

Abbreviations

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References