bims-mecosi 2026-07-12 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–07–12
fifteen papers selected by
Verena Kohler, Umeå University

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cancer: Hubs for Tumor Progression and Therapeutic Vulnerabilities.
Annexin A6 Is a Novel Cytosolic Regulator of Multiple Inter-organelle Contact Sites.
Structural Organization of the Nvj3-Mdm1 Complex Reveals a Conserved Lipid-Compatible Contact Site Module.
Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
MAM-Localized MANF Counteracts Microinflammatory Stress to Attenuate Mitochondrial Dysfunction and Cataractogenesis in High Myopia.
MFN2-Mediated MERCs Promote Odontoblast Differentiation and Dentinogenesis.
YdbL directly modulates YdbH-YnbE bridge formation to maintain Escherichia coli outer membrane homeostasis.
ER-mitochondria tether ML1 coordinates peripheral fission and wholesale mitophagy for plant adaptation to carbon starvation.
Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
Cryo-EM structure of soluble VPS13C suggests its regulation by a conformational switch and by calmodulin.
Remodeling of the mitochondrial quality control network: natural products intervening in diabetic retinopathy.
Sulforaphane protects cardiomyoblasts against chemical hypoxia by increasing mitochondrial-ER communication and autophagy.
MANF safeguards mitochondria-associated endoplasmic reticulum membrane integrity in nucleus pulposus-derived mesenchymal stem cells to maintain homeostasis of the intervertebral disc.
Mitochondrial-ER stress crosstalk in osteoarthritis: From ageing-associated chondrocyte dysfunction to emerging therapeutics.
Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.

Cell Biol Int. 2026 Jul;50(7): e70185

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cancer: Hubs for Tumor Progression and Therapeutic Vulnerabilities.

Linlin Yan, Shaoqing Liu, Kai Wu, Ming Gao, Dan Yan, Meiling Tian, Jing Xiao, Yang Yang, Bo Qin.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact sites between the endoplasmic reticulum (ER) and mitochondria that coordinate multiple cellular processes such as calcium signaling, lipid trafficking, and redox homeostasis. Increasing evidence shows that cancer cells remodel MAMs to support metabolic adaptation, stress tolerance, tumor progression, and therapeutic resistance. In this review, we summarize the structural organization of MAMs, the core tethering and regulatory mechanisms governing their plasticity, and emerging evidence linking MAM dysfunction to malignant phenotypes and therapeutic resistance. We highlight that the roles of MAM-associated proteins in cancer are highly context-dependent, varying with tumor type, metabolic state, and therapeutic pressure. We further discuss emerging therapeutic strategies targeting MAM-associated pathways, as well as combination approaches to overcome resistance. A better mechanistic understanding of MAM remodeling may reveal actionable vulnerabilities and support biomarker-guided precision therapy across cancer types.

Keywords:  calcium signaling; cancer; lipid metabolism; mitochondria‐associated endoplasmic reticulum membranes; therapeutic resistance

DOI:  https://doi.org/10.1002/cbin.70185
Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261466547

Annexin A6 Is a Novel Cytosolic Regulator of Multiple Inter-organelle Contact Sites.

Carlos Enrich, Carles Rentero, Thomas Grewal.

  Annexins are a widely expressed family of multifunctional cytosolic proteins with diverse cellular roles. Recent advances have uncovered new avenues for the involvement of several annexins in membrane dynamics, suggesting a potential link to the coordination of membrane contact site (MCS) formation. Up to date, Annexin A1 (ANXA1), ANXA6 and ANXA11 have been defined as MCS-associated annexins. In a recent study, we demonstrated that ANXA6 critically influences the formation of multiple inter-organelle contact sites. Using electron microscopy, proximity-labelling and proteomic assays, ANXA6 deficiency was shown to substantially reduce the extent and number of MCS between several organelles in a number of cell lines. This correlated with ANXA6 interacting with various tethers and bona fide MCS proteins that can modulate multi-organelle contacts, indicating that the loss of ANXA6-related protein-protein interactions reduced the ability to develop contacts between organelles. Importantly, restoration of ANXA6 expression in ANXA6-deficient cells re-established MCS numbers, suggesting that transient changes in ANXA6 expression levels significantly impact on MCS dynamics. These findings identify ANXA6 as the first example of a cytosolic protein whose expression levels directly modulate the cellular organization of MCS.

Keywords:  STARD3; actin-cytoskeleton; annexin A6; endolysosomes; membrane contact sites

DOI:  https://doi.org/10.1177/25152564261466547
bioRxiv. 2026 Jul 03. pii: 2026.06.29.735323. [Epub ahead of print]

Structural Organization of the Nvj3-Mdm1 Complex Reveals a Conserved Lipid-Compatible Contact Site Module.

Marwa Aboumourad, Hanaa Hariri.

Membrane contact sites are organized by protein assemblies that physically couple organelles and coordinate lipid metabolism, yet the structural principles that enable lipid exchange across these junctions remain poorly defined. At the nuclear-vacuolar junction (NVJ) in budding yeast, the tethering protein Mdm1 and its binding partner Nvj3 form a complex that regulates lipid metabolic pathways, but the structural features underlying their interaction have not been resolved. Here, we use AlphaFold-based complex prediction and comparative structural analysis to define the organization of Nvj3-Mdm1 complex assembly. We identify a high-confidence heterodimer in which conserved PXA and PXC domains generate an extended tunnel spanning both proteins. Tunnel analysis predicts a core hydrophobic conduit traversing the Nvj3-Mdm1 interface, consistent with a lipid-compatible architecture. Evolutionary conservation is enriched at the Nvj3-Mdm1 interface. The predicted conduit shares geometric and physicochemical properties with bridge-like lipid transfer proteins, including Atg2, Fmp27, and Hob2, suggesting that heteromeric tether assemblies may contribute directly to inter-organelle lipid transfer. Notably, this conduit is predicted to arise from a heteromeric α-helical assembly rather than the β-sheet-rich architecture characteristic of canonical bridge-like lipid transfer proteins. Comparative phylogenetic analyses showed that Nvj3 and Mdm1 share broadly congruent evolutionary patterns across Saccharomycetes, consistent with their conserved functional association. Together, these findings define Nvj3 as a structural partner of Mdm1 and support a conduit-based model of lipid transfer at the NVJ.

DOI: https://doi.org/10.64898/2026.06.29.735323
Aging Cell. 2026 Jul;25(7): e70624

Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.

Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.

  Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.

Keywords:  age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control

DOI:  https://doi.org/10.1111/acel.70624
Adv Sci (Weinh). 2026 Jul 08. e76342

MAM-Localized MANF Counteracts Microinflammatory Stress to Attenuate Mitochondrial Dysfunction and Cataractogenesis in High Myopia.

Xin Liu, Hao Li, Ching Kang, Dongling Guo, Shuyu Liu, Jiaqi Meng, Zhiqian Huang, Yu Du, Xiangjia Zhu.

  Chronic microinflammation drives tissue degeneration, particularly in age-related and metabolic diseases, yet how it disrupts inter-organelle communication that leads to cellular failure remains largely unexplored. Utilizing highly myopic cataract (HMC) as a paradigm, we uncover a non-canonical defense mechanism centered on mitochondria-associated endoplasmic reticulum membranes (MAMs). Under microinflammatory stress, mesencephalic astrocyte-derived neurotrophic factor (MANF), conventionally recognized as an ER-resident protein, specifically localizes to MAMs in lens epithelial cells (LECs). At this critical interface, MANF acts as a metabolic sensor that safeguards calcium homeostasis by directly promoting the ubiquitin-mediated degradation of the sarco/endoplasmic reticulum Ca2 +-ATPase 2 (SERCA2). Microinflammation-induced MANF deficiency triggers pathological SERCA2 accumulation, MAM hyperassembly, disrupted ER-to-mitochondria calcium coupling, profound oxidative stress, and mitochondrial bioenergetic collapse, culminating in LEC apoptosis. We validate this pathogenic cascade using human HMC specimens, a unilateral defocus-induced high myopia model, and a novel lens-specific Manf conditional knockdown mouse. Strikingly, in vivo AAV2-mediated MANF gene delivery successfully normalizes MAM architecture, rescues mitochondrial function, and prevents cataractogenesis, demonstrating therapeutic reversibility. In summary, this study establishes the MANF-SERCA2 axis at the MAM interface as a critical pathway linking microinflammation to organelle dysfunction and proposes this interaction as a promising therapeutic target for cataractogenesis and other microinflammation-driven degenerations.

Keywords:  MANF; SERCA2; highly myopic cataract; microinflammation; mitochondria‐associated ER membranes (MAMs)

DOI:  https://doi.org/10.1002/advs.76342
J Dent Res. 2026 Jul 09. 220345261458702

MFN2-Mediated MERCs Promote Odontoblast Differentiation and Dentinogenesis.

J Sheng, L Yan, Z Chen, G Yang, G Yuan.

  Odontoblasts are a tooth-specific cell type responsible for dentin formation. During odontoblast differentiation, dramatic organelle alterations occur with the increase of both mitochondria and endoplasmic reticulum (ER). In multiple cell types, mitochondria-ER contact sites (MERCs) are formed to regulate cellular biological processes via mediating essential interorganelle communications. However, whether MERCs play a role in odontoblast differentiation remains enigmatic. Here, we found a progressive increase of MERCs during the in vitro odontoblastic differentiation using live-cell imaging, transmission electron microscopy (TEM), and in situ proximity ligation assay (PLA). Meanwhile, in situ PLA verified the in vivo elevation of MERCs in the odontoblasts of mouse teeth. Remarkably, the disruption of MERCs via overexpression of FATE1, a protein that increases the distance between mitochondria and ER, suppressed the expression of key odontoblast markers, alkaline phosphatase (ALP) activity, and mineralized nodule formation in the mouse dental papilla cells (mDPCs) after differentiation induction, suggesting a positive role of MERCs for odontoblastic differentiation. Among all MERC-associated genes, Mfn2 expression is significantly increased in the RNA sequencing data of odontoblast-like cells versus undifferentiated mDPCs. Further experiments showed that knockdown of Mfn2 resulted in diminished MERC formation as well as impaired odontoblastic differentiation, as evidenced by the downregulated expression of odontoblast markers, compromised ALP activity, and mineralized nodule formation. The impaired odontoblastic differentiation upon Mfn2 knockdown was rescued by the overexpression of Linker, an enhancer of MERC formation, suggesting that MFN2 enhances MERC formation to promote odontoblastic differentiation. Consistently, in vivo knockdown of Mfn2 also impaired MERC formation as well as odontoblast differentiation and dentinogenesis, which were restored by in vivo Linker overexpression. Taken together, these findings indicate that MERCs are dynamically increased and essential for odontoblast differentiation and dentinogenesis with MFN2 as an essential mediator, which provides an important mechanism of organelle interaction orchestrating odontoblast differentiation.

Keywords:  cell differentiation; dentin; mitochondria-associated membranes; odontoblasts; odontogenesis; organelles

DOI:  https://doi.org/10.1177/00220345261458702
mBio. 2026 Jun 29. e0070026

YdbL directly modulates YdbH-YnbE bridge formation to maintain Escherichia coli outer membrane homeostasis.

Clare De'Ath, Sujeet Kumar, Sachi Chhibber, Benjamin F Cooper, Emilia K Taylor, Emily Jones, Thomas Lanyon-Hogg, Jani R Bolla, Christina Redfield, Natividad Ruiz, Georgia L Isom.

  Gram-negative bacteria pose a threat to global healthcare mainly because their outer membrane (OM) provides an intrinsic barrier to many antimicrobials. Key to this barrier function is the asymmetric structure of the OM, with phospholipids constituting the inner leaflet and lipopolysaccharides, the outer leaflet. Although the mechanism of phospholipid transport between the inner membrane (IM) and OM remains poorly understood, recent studies implicate TamB, YhdP, and YdbH as functionally redundant proteins mediating this process in Escherichia coli. Accordingly, the collective loss of these three paralogs is lethal, and any one of them is sufficient for growth. YdbH is anchored to the IM, and its periplasmic repeating β-sheet groove domain interacts with the OM lipoprotein YnbE via β-strand augmentation to form an intermembrane bridge. Additionally, YnbE multimerizes, and the periplasmic protein YdbL is proposed to modulate YnbE multimerization to facilitate its stacking on the C-terminus of YdbH. Here, we demonstrate that excess YdbL specifically inhibits the function of the YdbH-YnbE complex since overexpression of ydbL causes lethality in the ΔyhdP ΔtamB double mutant, but the presence of both ydbH and ynbE in trans abrogates this lethality. We resolve high-resolution structural data for YdbL and ascertain its interaction site with the YnbE C-terminal α-helix, with residues mediating this interface highly conserved and critical for YdbL function. Finally, we show that YdbL is protected from degradation by the protease DegP when complexed with YnbE. Overall, our data support a model in which YdbL ensures proper YdbH-YnbE intermembrane bridge formation by directly interacting with YnbE.
IMPORTANCE: The mechanism underlying phospholipid transport between the inner and outer membranes of gram-negative bacteria remains enigmatic. Bacterial bridge-like protein systems such as the YdbH-YnbE complex resemble proteins found at membrane contact sites between eukaryotic organelles. These proteins are proposed to mediate intermembrane phospholipid transport, which is essential for growth of the outer membrane (OM). Here, we define the role of YdbL, a periplasmic protein that specifically modulates the YdbH-YnbE system. YdbL directly interacts with YnbE and controls the formation of the YdbH-YnbE complex. Additionally, we reveal that YdbL is selectively degraded by the periplasmic protease DegP. We propose a regulatory model that connects the YdbH-YnbE complex assembly and controls the levels of YdbL, providing new insight into OM homeostasis in gram-negative bacteria.

Keywords:  AsmA-like proteins; outer membrane biogenesis; phospholipid transport

DOI:  https://doi.org/10.1128/mbio.00700-26
Sci Adv. 2026 Jul 10. 12(28): eaef6631

ER-mitochondria tether ML1 coordinates peripheral fission and wholesale mitophagy for plant adaptation to carbon starvation.

Benhui Shi, Baolei Li, Songyang Wang, Xu Zhang, Yu Tang, Jun Jiang, Liting Zhai, Yang Shao, Jiaqi Sun.

Plants frequently encounter carbon starvation from extended darkness or canopy shading or in nonphotosynthetic tissues, requiring rapid mitochondrial remodeling to match reduced metabolic flux. Here, we reveal a coordinated program integrating peripheral fission-mediated damage segregation and wholesale mitophagy. Carbon starvation triggers a shift from symmetric midzone fission to asymmetric peripheral fission, generating small depolarized fragments alongside larger polarized mitochondria. Unexpectedly, damage-independent wholesale mitophagy targets medium-sized mitochondria for both burden reduction and resource mobilization while excluding small peripheral fission products. We identify mitochondria-ER (endoplasmic reticulum) linker 1 (ML1), a carbon starvation-inducible ER-mitochondria tether, as the central coordinator. At ER-mitochondria contact sites, ML1 promotes peripheral fission and recruits ATG18a (autophagy-related protein 18a) for wholesale mitophagy. Loss of ML1 impairs this coordinated remodeling, resulting in elongated mitochondria, compromised function, and hypersensitivity to carbon starvation. These findings reveal how plants achieve rapid metabolic adaptation through coordinated mitochondrial remodeling.

DOI: https://doi.org/10.1126/sciadv.aef6631
Brain Behav. 2026 Jul;16(7): e71418

Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.

Tianyi Gu, Hangyan Guo, Zixin Guo, Shengyu Hua.

   INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD.
METHODS: A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis.
RESULTS: The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (Aβ) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death.
CONCLUSION: Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates Aβ/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.

Keywords:  Alzheimer's disease; inflammation; mitochondrial dysfunction; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1002/brb3.71418
Mol Cell. 2026 Jul 07. pii: S1097-2765(26)00417-X. [Epub ahead of print]

Cryo-EM structure of soluble VPS13C suggests its regulation by a conformational switch and by calmodulin.

Dazhi Li, Xinbo Wang, Hongyan Hao, Jessica Eden, Bodan Hu, Emma E Walsh, Matthew A H Parson, Stephanie Hamill, Yuting Li, Guochao Chen, John E Burke, Pietro De Camilli, Karin M Reinisch.

  Bridge-like lipid transfer proteins (BLTPs) play fundamental roles in cellular lipid redistribution between organellar membranes. They comprise bridge domains spanning organelles at contact sites that allow lipids to transit through the cytosol between adjacent membranes. The assembly of BLTPs into complexes with adaptor proteins enables lipid transfer. To address the mechanisms underlying the assembly and regulation of BLTP complexes, we used cryo-EM to resolve the structure of one such BLTP, the Parkinson's disease protein VPS13C, at near-atomic resolution. The structure identifies a lipid-transfer-nonpermissive conformation, in which the built-in C-terminal VAB adaptor module blocks the end of the lipid transfer bridge, interfering with lipid delivery. We also identify calmodulin (CaM), central to calcium signaling, as a constitutive VPS13C interactor. Calcium induces conformational changes in the VPS13C-CaM complex, suggesting calcium regulation of VPS13 function. Altogether, this structure of intact VPS13C serves as a starting point for understanding its regulation and that of other VPS13 proteins.

Keywords:  lipid transport; lysosomes, PARK23, Parkinson's disease, BLTP; membrane homeostasis

DOI:  https://doi.org/10.1016/j.molcel.2026.06.028
Front Pharmacol. 2026 ;17 1851846

Remodeling of the mitochondrial quality control network: natural products intervening in diabetic retinopathy.

Tingru Chen, Ruolan Wu, Xinyi Liu, Yutong Jiang, Qun Huang, Ninghui Wan.

  Diabetic retinopathy (DR) remains a leading cause of vision loss among working-age adults. Its pathogenesis is increasingly understood as the progressive dysregulation of the mitochondrial quality control (MQC) network, which encompasses mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondria-associated endoplasmic reticulum membranes (MAMs), and intercellular mitochondrial transfer. Under sustained hyperglycemia, this network shifts from compensatory imbalance to irreversible collapse, driving mitochondrial dysfunction, oxidative stress, inflammatory activation, and retinal neurovascular unit (NVU) injury, thus promoting progression from non-proliferative to proliferative DR. Because of their multitarget properties, natural products (NPs) can restore fusion-fission balance, modulate mitophagy in a stage-dependent manner, and promote mitochondrial biogenesis, thereby remodeling the MQC network. However, their clinical translation is constrained by low bioavailability, poor penetration of the blood-retinal barrier (BRB), and potential dose-dependent toxicity. Mitochondria-targeted nano-delivery systems, including liposomes, exosomes, and mitochondrial-derived vesicles, may improve retinal accumulation and mitochondrial targeting. Future studies should refine stage-specific mechanistic understanding, strengthen safety evaluation and structural optimization, and integrate single-cell omics with artificial intelligence to accelerate translation and enable early MQC-targeted intervention, with the potential to delay or even reverse the progression of DR. Critically, MQC-directed NP therapy should not be interpreted as uniformly pro-mitophagy, anti-fission, or pro-biogenesis; the therapeutic benefit depends on disease stage, cell type, autophagic flux integrity, target engagement, and retinal pharmacokinetic/pharmacodynamic exposure.

Keywords:  diabetic retinopathy; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; natural products

DOI:  https://doi.org/10.3389/fphar.2026.1851846
Chem Biol Interact. 2026 Jul 07. pii: S0009-2797(26)00347-9. [Epub ahead of print]437 112239

Sulforaphane protects cardiomyoblasts against chemical hypoxia by increasing mitochondrial-ER communication and autophagy.

Gabriela Navarrete-Anastasio, Edith Álvarez-León, Angélica Ruiz-Ramírez, Elizabeth Soria-Castro, Wylly Ramsés García-Niño, Israel Pérez-Torres, Rebeca López-Marure, Cecilia Zazueta, Alejandro Silva-Palacios.

  Disruption of the contact sites between mitochondria and the endoplasmic reticulum (MERCSs) adversely affects cardiomyocyte function, necessitating interventions to preserve these connections and maintain the cellular homeostasis. Currently, the nutraceutical sulforaphane (SFN) has emerged as a promising candidate for enhancing MERCSs communication and offering protection in various contexts. In this study, we investigated whether SFN preserves MERCSs functionality in cardiomyoblasts subjected to cobalt chloride (CoCl2)-induced chemical hypoxia. We explored cellular events, including oxidative stress, endoplasmic reticulum stress (ERS), and autophagy, which are regulated by MERCSs. Our findings confirmed that in rat cardiomyoblasts H9c2 pretreated with SFN and exposed to CoCl2, mitochondrial-ER associations were maintained, facilitating the formation of autophagolysosomes. This suggest that autophagy is a mechanism through which SFN protects cardiomyoblasts under chemical hypoxia. This study underscores the significance of MERCSs as functional platforms for maintaining cellular homeostasis and highlights their potential as strategic targets for mitigating the harmful effects of hypoxia in cardiomyoblasts.

Keywords:  Autophagy; Cardiomyoblasts; Cobalt chloride; ER stress; Hypoxia; MERCSs; Oxidative stress; Sulforaphane

DOI:  https://doi.org/10.1016/j.cbi.2026.112239
Cell Biol Toxicol. 2026 Jul 09.

MANF safeguards mitochondria-associated endoplasmic reticulum membrane integrity in nucleus pulposus-derived mesenchymal stem cells to maintain homeostasis of the intervertebral disc.

Chenhao Zhao, Liang Kang, Jiaqi Wang, Yanxin Wang, Yu Chen, Luping Zhou, Chongyu Jia, Huaqing Zhang, Jingyu Zhang, Zhiwei Chen, Renjie Zhang, Cailiang Shen.

   BACKGROUND: Intervertebral disc (IVD) degeneration (IDD) is a leading cause of low back pain, with limited treatment options. The degenerative disc's harsh microenvironment promotes nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) death and hinders self repair. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an atypical neurotrophic factor, has protective effects in degenerative diseases. However, its role in IDD is unclear.
METHODS: Assessment of MANF expression was conducted in both human nucleus pulposus tissues and a rat IVD puncture model. An in vitro model of degeneration was established by acid treatment of NP-MSCs, and the functional role of MANF was explored through its knockdown and overexpression. RNA sequencing was employed to identify downstream targets. The therapeutic potential of MANF-overexpressing NP-MSCs was evaluated in a rat puncture model.
RESULTS: MANF expression was markedly downregulated in degenerated IVD tissues from both human patients and rat models. Correspondingly, in vitro experiments demonstrated that MANF knockdown exacerbated, while its overexpression mitigated, acid-induced apoptosis of NP-MSCs. Mechanistically, MANF attenuated mitochondrial dysfunction and ER stress of NP-MSCs under acidic conditions by maintaining MAM integrity, as demonstrated by the complete abolition of this protection upon treatment with the MAM uncoupler FATE1. Transcriptomic analysis and subsequent validation identified receptor expression-enhancing protein 1 (REEP1) as a critical downstream effector through which MANF safeguards MAM integrity. We further elucidated that MANF upregulates REEP1 expression by directly inhibiting miR-33b-5p. In vivo, transplantation of MANF-overexpressing NP-MSCs effectively attenuated IDD in a rat model.
CONCLUSION: MANF protected NP-MSCs from acidosis by sustaining MAM integrity via the MiR-33b-5p/REEP1 axis. These findings reveal MANF's mechanism and therapeutic potential for IDD.

Keywords:  Acid microenvironment; Intervertebral disc degeneration; Mesencephalic astrocyte-derived neurotrophic factor; Mitochondria-associated endoplasmic reticulum membrane; Nucleus pulposus-derived mesenchymal stem cells

DOI:  https://doi.org/10.1007/s10565-026-10226-8
Ageing Res Rev. 2026 Jul 10. pii: S1568-1637(26)00244-8. [Epub ahead of print]121 103252

Mitochondrial-ER stress crosstalk in osteoarthritis: From ageing-associated chondrocyte dysfunction to emerging therapeutics.

Md Meraj Ansari, Godagama Gamaarachchige Dinesh Suminda, Rehan Khan, Young-Ok Son.

  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.

Keywords:  Aging; Endoplasmic reticulum stress; Mitochondrial dysfunction; Osteoarthritis; Oxidative stress; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.arr.2026.103252
Protein Sci. 2026 Aug;35(8): e70703

Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.

Lena J Reichert, F-Nora Vögtle, Carlotta Peselj.

  Mitochondria respond to proteotoxic stress through the mitochondrial unfolded protein response, traditionally viewed as a transcriptional program that restores proteostasis by inducing chaperones and proteases. Emerging evidence indicates that mitochondrial membrane remodeling constitutes an additional adaptive component of this response. Regulated changes in mitochondrial lipid composition, particularly involving the signature phospholipid cardiolipin, support mitochondrial function during stress by stabilizing protein import machineries, promoting mitochondrial protein biogenesis, and facilitating recovery from dysfunction. In addition, stress originating in other organelles, especially the endoplasmic reticulum, reshapes mitochondrial membranes through altered lipid biosynthesis, inter-organelle lipid trafficking, and stress signaling pathways. These findings suggest that mitochondrial membrane remodeling represents a regulatory layer of organelle quality control integrated within interconnected stress response networks and may provide new opportunities to enhance mitochondrial resilience in disease.

Keywords:  ER–mitochondria crosstalk; cardiolipin; mitochondrial membrane remodeling; mitochondrial protein biogenesis; mitochondrial unfolded protein response (UPRmt); organelle stress signaling

DOI:  https://doi.org/10.1002/pro.70703