bims-mecosi 2026-01-18 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–01–18
sixteen papers selected by
Verena Kohler, Umeå University

Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.
Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.
Mitochondria-ER crosstalk via MAMS: Bridging cellular homeostasis and cancer progression.
Signaling architecture of the glucagon-like peptide-1 receptor.
Natural products modulate mitochondria-associated membranes to prevent cardiovascular diseases.
VAPA at the inner nuclear membrane affects nuclear lamins and nuclear morphology.
Chronic ER Stress Disrupts Mitochondrial-Associated ER Membrane Integrity in Corneal Endothelial Cells.
Nvj3 regulates Dga1-mediated triacylglycerol synthesis and lipid droplet formation at ER contact sites.
Ocular Risks of Spaceflight and a Path to Prevention: Targeting Mitochondria-ER Stress With Low-Intensity Ultrasound.
Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.
Liquid liquid phase separation of the intrinsically disordered protein JPT2 compartmentalizes components of NAADP-evoked Ca 2+ signaling.
Molecular insights into bulk lipid transport from structural studies of the bridge-like protein VPS13A complexed with the scramblase XKR1.
A shared binding interface controls Vps13 organelle-specific targeting independently of its vacuolar protein sorting function.
Unveiling the neuroprotective power of mitochondrial transfer in orofacial inflammatory pain through ER membrane remodeling.
Hypoxia-conditioned BMSC exosomes improve short-term spinal cord injury outcomes via the miR-615-3p/PDE4C-mediated cAMP/PKA pathway.
Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.

Cell Mol Biol Lett. 2026 Jan 11.

Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.

Pavitra Kumar, Mohsin Hassan, Frank Tacke, Cornelius Engelmann.

  Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca2+), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence-such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype-are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.

Keywords:  Calcium; Contact sites; ER; Hepatocyte; MERCs; Mitochondria; Senescence

DOI:  https://doi.org/10.1186/s11658-025-00809-4
Int J Biol Sci. 2026 ;22(2): 731-749

Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.

Nai-Jia Xue, Yi Liu, Zhi-Hao Lin, Wen-Hao Huang, Feng Zhang, Ran Zheng, Xiao-Li Si, Lu-Yan Gu, Yi Fan, Jia-Li Pu, Bao-Rong Zhang.

  Disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium homeostasis has been implicated in the pathogenesis of Parkinson's disease (PD). Parkin, a PD-associated E3 ubiquitin ligase, has been shown to regulate MAM integrity and calcium dynamics. However, the mechanisms of Parkin recruitment and its substrate specificity have not been well understood. This investigation has demonstrated that loss of Parkin enhances ER-mitochondria associations and leads to excessive calcium flux in MAM, resulting in abnormal mitochondrial permeability transition pore (mPTP) opening and decreased cell viability. Further, Parkin physically interacts with IP3R-Grp75-VDAC1 complex at ER-mitochondria contact sites, where it is recruited by IP3R-mediated calcium flux and mitophagy. More importantly, Parkin deficiency leads to the accumulation of IP3R levels, particularly in MAM region. In addition, Parkin fine-tunes the stability of the complex and ubiquitinates IP3R for degradation via the ubiquitin-proteasomal system, ensuring suitable calcium transfer. Taken together, our study reveals a novel role of Parkin in regulating ER-mitochondria contacts, providing insights into PD pathogenesis and potential therapeutic strategies targeting MAMs.

Keywords:  IP3R; Parkin; calcium; mitochondria-associated ER membrane; ubiquitination

DOI:  https://doi.org/10.7150/ijbs.121759
Apoptosis. 2026 Jan 12. 31(1): 43

Mitochondria-ER crosstalk via MAMS: Bridging cellular homeostasis and cancer progression.

Rohan Roy, Arghya Adhikary, Rudranil De, Swatilekha Ghosh.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact points between the endoplasmic reticulum (ER) and mitochondria, governing essential cellular processes such as calcium (Ca²⁺) signaling, lipid metabolism, mitochondrial dynamics, and apoptosis. The effective movement of Ca²⁺ from the ER to mitochondria at MAMs is crucial for sustaining bioenergetics and controlling cell fate outcomes like survival or programmed cell death. Recent findings highlight the importance of MAMs in maintaining cellular balance and demonstrate their functional versatility in both healthy and diseased states. Disruption of MAM integrity and signaling is increasingly linked to the development of various diseases, including cancer. In cancer, MAMs demonstrate two regulatory roles- either promoting oncogenic functions or enhancing tumor-suppressive actions based on the molecular context and cellular environment. Changes in the structural framework of MAMs, such as variations in protein makeup and tethering distance between the ER and mitochondria, have been directly linked to several characteristics of tumor formation. Therefore, a deeper understanding of the molecular components and regulatory mechanisms governing MAM function may offer a promising avenue for the development of novel therapeutic strategies aimed at restoring proper organelle communication and counteracting cancer development and progression.

Keywords:  Autophagy; Calcium signaling; Endoplasmic reticulum stress; Lipid metabolism; Mitochondria-associated membranes

DOI:  https://doi.org/10.1007/s10495-025-02252-4
J Clin Invest. 2026 Jan 16. pii: e194752. [Epub ahead of print]136(2):

Signaling architecture of the glucagon-like peptide-1 receptor.

Gregory Austin, Alejandra Tomas.

The glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor and major therapeutic target in type 2 diabetes and obesity. Beyond its canonical role in Gαs/cAMP signaling, GLP-1R is increasingly recognized as an organizer of spatiotemporally defined signaling nanodomains, or "signalosomes." This Review highlights our current knowledge on the mechanisms of assembly and regulation of GLP-1R signalosomes, including the involvement of biomolecular condensates formed by liquid-liquid phase separation, and the role of membrane contact sites between the endoplasmic reticulum (ER) and other organelles as key locations for GLP-1R signaling assemblies. Furthermore, we discuss existing data on the molecular composition and functional impact of two predicted GLP-1R nanodomains, one at ER-plasma membrane contact sites, where GLP-1R might interact with ion channels and transporters to influence local excitability and coordinated insulin secretion, and another at ER-mitochondria membrane contact sites, with the capacity to control lipid and calcium signaling and modulate ER and/or mitochondrial activity. We additionally discuss the role of GLP-1R posttranslational modifications as critical modulators of GLP-1R signal specification and nanodomain organization. Conceptualizing GLP-1R as a dynamic architect of spatiotemporally encoded signalosomes opens new avenues for a deeper understanding of incretin biology with the potential for identification of novel GLP-1R effectors and the development of refined therapeutic strategies for metabolic disease.

DOI: https://doi.org/10.1172/JCI194752
Phytomedicine. 2026 Jan 06. pii: S0944-7113(26)00023-1. [Epub ahead of print]151 157786

Natural products modulate mitochondria-associated membranes to prevent cardiovascular diseases.

Yuefang Zhang, Bo Ning, Weiwei He, Kai Wang, Hongyu Chen, Zhan Zhang, Zhiru Zhang, Lihong He, Yuxuan Lei, Mingjun Zhao, Yao Liu.

   BACKGROUND: Cardiovascular disease (CVD) represents a leading global cause of morbidity and mortality, and its prevalence and associated mortality are projected to rise significantly alongside the aging of the population. Aging, as a primary and non-modifiable risk factor, contributes to the progressive decline in cardiovascular structure and function, thereby predisposing individuals to a spectrum of CVDs, including coronary artery disease (CAD), heart failure (HF), and hypertension. A growing body of experimental evidence indicates that mitochondrial and endoplasmic reticulum (ER) dysfunction serves as a key driver in the onset and development of CVD. The mitochondria-associated membrane (MAM), a specialized subcellular domain, mediates the critcal communication between these two organelles. Functioning as both a physical tether and a functional platform, the MAM regulates essential cellular processes and has been implicated in the pathogenesis of CVD. Current conventional pharmacotherapies for CVD, while effective, are often associated with potential side effects and typically involve complex, long-term medication regimens that necessitate regular monitoring and therapeutic adjustments. In contrast, natural products (NPs), underpinned by unique theoretical frameworks and extensive postive clinical experience, offer patients a complementary and differentiated therapeutic choice.
PURPOSE: This article systematically reviews the role of action of MAM in the pathophysiology of CVD and explores its potential as a therapeutic target. Furthermore, it examines the regulatory effects of NPs on mitochondria-endoplasmic reticulum interactions and the cardioprotective effect exerted by targeting MAM.
METHODS: The search terms "cardiovascular diseases", "mitochondria", "endoplasmic reticulum", "mitochondria-associated membranes", "mitochondria-associated endoplasmic reticulum membranes", "natural products", "traditional Chinese medicine", "mitochondrial dynamics", "lipid metabolism", "calcium", "apoptosis", "autophagy", "inflammation" and "oxidative stress" were used to search for studies published in the past five years until August 2025.
RESULTS: Studies have shown that MAM plays a pivotal role in the pathogenesis of CVD, including atherosclerosis (AS), myocardial ischemia/reperfusion injury (MI/RI), HF, and arrhythmia. By maintaining the normal function of mitochondria and the ER and enhancing their interaction, MAM serves as a key mechanism in protecting cardiovascular health.
CONCLUSION: NPs encompass a wide range of substances, including Chinese herbs, traditional Chinese medicine (TCM) monomeric compounds, compound TCM prescriptions, and traditional Chinese patent medicines. By targeting MAM, NPs demonstrate significant efficacy in alleviating clinical symptoms in patients with CVD. Furthermore, NPs are characterized by their favorable safety profile and low incidence of adverse effects. Collectively, this evidence underscores the considerable therapeutic potential of NPs as promising candidate drugs for CVD treatment. It also highlights the pivotal role of MAM in the pathogenesis of CVD, establishing it as a key therapeutic target for future drug development.

Keywords:  Cardiovascular diseases; Mitochondria-associated membranes; Natural products

DOI:  https://doi.org/10.1016/j.phymed.2026.157786
J Cell Sci. 2026 Jun 15. pii: jcs264298. [Epub ahead of print]139(12):

VAPA at the inner nuclear membrane affects nuclear lamins and nuclear morphology.

Inés Rodríguez-González, David Kohlhause, Christof Lenz, Henning Urlaub, Christiane Spillner, Ralph H Kehlenbach.

  Vesicle-associated membrane protein-associated protein A (VAPA) is a protein of the endoplasmic reticulum (ER) and a component of several membrane contact sites (MCSs). We show here that VAPA also localizes to the inner nuclear membrane (INM), in close proximity to nuclear lamins, INM proteins and nucleoporins. Using our proteomics approach 'rapamycin- and APEX-dependent identification of proteins by SILAC' (RAPIDS), we identified several nuclear proximity partners of VAPA, including emerin, different LAP2 isoforms, lamin A/C and Nup153. Depletion of VAPA in various cellular systems resulted in reduced nuclear lamin levels and aberrant nuclear morphology, including the formation of membrane invaginations and tunnels. Furthermore, histone acetylation levels were altered. Our data suggest that VAPA has distinct nuclear functions, in addition to its established role as an ER organizer.

Keywords:  Endoplasmic reticulum; Inner nuclear membrane; Nuclear envelope; Nuclear tunnels; Nucleus; VAPA

DOI:  https://doi.org/10.1242/jcs.264298
bioRxiv. 2026 Jan 10. pii: 2026.01.09.698664. [Epub ahead of print]

Chronic ER Stress Disrupts Mitochondrial-Associated ER Membrane Integrity in Corneal Endothelial Cells.

Stephanie Lee, Stefan Y Kim, H Orhan Akman, Saba Qureshi, Anisha Kasi, William Steidl, Lukas Ritzer, Mariane Price, Francis W Price, Eric A Schon, Varun Kumar.

Purpose: Fuchs' endothelial corneal dystrophy (FECD) is an age-related degenerative disease of the corneal endothelium cells (CEnCs), affecting 4% of the US population over 40. While Endoplasmic reticulum (ER) and mitochondrial stress have been independently associated with FECD pathogenesis, few studies have examined ER-mitochondrial interactions/ER-mitochondrial contact sites/mitochondria-associated ER membrane (MAM), or MAM proteins, and their contribution to ER and mitochondrial stress in FECD. This study aims to characterize alterations in MAMs and identify key MAM proteins associated with ER and mitochondrial stress in FECD.
Method: Human corneal endothelial cell line (HCEnC-21T) and Fuchs' corneal endothelial cell line (F35T) were cultured and subjected to ER stressor tunicamycin (1, 10 μg/ml) for 6 and 24 hours. MAM proteins were isolated by subcellular fractionation, and key ER and mitochondrial-damage-sensor proteins, such as PERK and Parkin, respectively, were identified by immunoblotting. ER-mitochondrial contact sites were quantified using the MAM plasmid and transmission electron microscopy (TEM) in normal and Fuchs cell lines, as well as in human tissues under chronic ER stress.
Results: ER-mitochondrial contact distance significantly increased in Fuchs tissues compared with normal tissues, and a similar increase was observed in 21T cell line after tunicamycin treatment. There was a significant increase in the intensity of the MAM plasmid upon tunicamycin treatment at 6 hours in the 21T cell line compared to the non-treated control. However, MAM plasmid intensity significantly decreased at 24 hours compared to 6 hours post-tunicamycin treatment in 21T cell line. Analysis of MAM function by quantifying phosphatidylserine synthase 1 (PSS1 [gene PTDSS1]) expression in 21T cells showed a reduction in PTDSS1 expression after 24 hours of tunicamycin treatment. ER stress protein PERK and mitochondria damage sensor protein (Parkin) significantly increased in the MAM fraction after tunicamycin at 24 hours in 21T cell line.
Conclusions: Fuchs cell lines and tissues demonstrate decreased ER-mitochondrial interactions/MAMs, which are also seen in 21T cell line after chronic ER stress. Under chronic ER stress, ER and mitochondrial stress mediator proteins are translocated to MAM. This study highlights the importance of MAMs as a potential mediator of ER-mitochondria crosstalk in degenerating corneal endothelial cells for FECD.

DOI: https://doi.org/10.64898/2026.01.09.698664
bioRxiv. 2026 Jan 09. pii: 2026.01.05.695145. [Epub ahead of print]

Nvj3 regulates Dga1-mediated triacylglycerol synthesis and lipid droplet formation at ER contact sites.

Daniel Adebayo, Eseiwi Obaseki, Scott Miller, Marwa Aboumourad, Zaid Saadeh, Zachary Pomicter, Lindsey Kreinbring, Mohamad Rahal, Kashvi Vasudeva, Garrett Frost, Reema Smadi, Hanaa Hariri.

Lipid droplet (LD) biogenesis is essential for lipid homeostasis during nutrient stress, yet how lipid intermediates are spatially organized to support efficient triacylglycerol (TAG) synthesis remains unclear. Here, we identify Nvj3 as a nutrient-responsive regulator that links diacylglycerol (DAG) availability to TAG synthesis and LD formation at the endoplasmic reticulum (ER). Nvj3 is induced by glucose depletion and recruited to LD-associated ER domains. Loss of Nvj3 causes neutral lipid accumulation under steady state conditions but delays TAG synthesis under acute inducible metabolic transitions. Using controlled TAG induction systems, we show that Nvj3 is required to couple Dga1-dependent TAG synthesis to LD formation. In the absence of Nvj3, TAG accumulates but remains inefficiently packaged into LDs. Consistent with this defect, nvj3Δ cells exhibit altered phospholipid remodeling and mislocalization of DAG away from ER domains during starvation. Together, these findings establish Nvj3 as an organizer of lipid availability during metabolic stress and suggest that spatial control of DAG is a key determinant of LD biogenesis.
Summary: This study identifies Nvj3 as a spatial organizer of Dga1-dependent lipid droplet formation. Nvj3 promotes proper diacylglycerol positioning, and enables efficient triacylglycerol synthesis during metabolic stress. We propose that Nvj3 regulates lipid flux through spatial compartmentalization of diacylglycerol at membrane contact site-associated ER domains.

DOI: https://doi.org/10.64898/2026.01.05.695145
FASEB J. 2026 Jan 31. 40(2): e71462

Ocular Risks of Spaceflight and a Path to Prevention: Targeting Mitochondria-ER Stress With Low-Intensity Ultrasound.

Jee Hoon Lee, Hankyung Kim, Dae Yu Kim.

  The cornea is highly susceptible to spaceflight-induced stress, compromising visual acuity and mission safety. Here, we identify endoplasmic reticulum (ER) and mitochondrial dysfunction as key mediators of corneal degeneration under simulated microgravity (SMG). SMG exposure led to corneal epithelial thinning, reduced nerve fiber density, and delayed wound healing. Multi-omics profiling and cellular assays revealed aberrant ER-mitochondrial crosstalk, characterized by excessive formation of mitochondria-associated membranes (MAMs) and activation of stress signaling pathways. Notably, treatment with low-intensity ultrasound (LIUS) restored corneal epithelial integrity by modulating MAM dynamics, alleviating organelle stress, and normalizing cellular homeostasis. These findings identify a novel molecular axis in microgravity-induced ocular degeneration and propose LIUS as a deployable, non-invasive countermeasure for preserving corneal health during deep spaceflight.

Keywords:  corneal degeneration; endoplasmic reticulum (ER) stress; inter‐organelle communication; low‐intensity ultrasound (LIUS); microgravity; mitochondrial dysfunction; mitochondria‐associated membranes (MAMs); spaceflight

DOI:  https://doi.org/10.1096/fj.202502831RR
Nat Commun. 2026 Jan 15.

Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.

Tim Vervliet, Jens Loncke, Marko Sever, Karan Ahuja, Chris Van den Haute, Tomas Luyten, Grace E Stutzmann, Catherine Verfaillie, Tihomir Tomašič, Geert Bultynck.

Lysosomal and endoplasmic reticulum (ER) Ca2+ release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca2+ release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H+-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain unknown. Here, we show that RyRs interact with the ATP6v0a1 subunit of the vATPase, contributing to ER-lysosomal contact site formation. This interaction suppresses RyR-mediated Ca²⁺ release, leading to reduced lysosomal exocytosis. Pharmacological inhibition of RyR activity mimics these effects on lysosomal exocytosis. Retaining lysosomes inside cells via RyR inhibition increases ER-lysosomal contact site formation, rendering lysosomes more available for autophagic flux. In summary, these findings establish RyR/ATP6v0a1 complexes as ER-lysosomal tethers that dynamically and Ca2+ dependently regulate the intracellular availability of lysosomes to participate in autophagic flux.

DOI: https://doi.org/10.1038/s41467-025-68054-z
bioRxiv. 2026 Jan 11. pii: 2026.01.10.698830. [Epub ahead of print]

Liquid liquid phase separation of the intrinsically disordered protein JPT2 compartmentalizes components of NAADP-evoked Ca 2+ signaling.

Sushil Kumar, Gihan S Gunaratne, Jasmine Cornish, Kirsten M Silvey, Qianru Mu, Zhong Guan, Gabriella T Heller, James T Slama, Sandip Patel, Jonathan S Marchant.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca 2+ -releasing second messenger that activates two-pore channels (TPCs) on endosomes and lysosomes. Rather than binding TPCs directly, NAADP acts through cytoplasmic NAADP-binding proteins (NAADP-BPs) which are essential for endolysosomal Ca 2+ release. Here we characterized the properties of two recombinant, purified NAADP-BPs: Jupiter Microtubule Associated Homolog 2 (JPT2) and like-Sm protein 12 (LSM12). In contrast to LSM12, JPT2 is predicted to be an intrinsically disordered protein, a feature confirmed by circular dichroism and NMR spectroscopy. Under conditions of low Na + concentration or molecular crowding, JPT2 underwent phase separation, as demonstrated by multiple orthogonal approaches. JPT2 condensates displayed liquid-like behavior and efficiently recruited LSM12, a novel fluorescent NAADP analog, as well as tubulin. JPT2 condensates also interacted with polymerized microtubules and lysosomes isolated from human cell lines. These findings reveal an unexpected capability of NAADP-BPs to undergo phase separation, and segregate with components needed for NAADP-dependent Ca 2+ release. We speculate that these signaling condensates dictate cellular NAADP sensitivity, desensitization of NAADP responses, as well as NAADP targeting to TPCs at membrane contact sites between acidic organelles and the endoplasmic reticulum.

DOI: https://doi.org/10.64898/2026.01.10.698830
bioRxiv. 2026 Jan 08. pii: 2026.01.07.698282. [Epub ahead of print]

Molecular insights into bulk lipid transport from structural studies of the bridge-like protein VPS13A complexed with the scramblase XKR1.

Bodan Hu, Daniel Alvarez, Cristian Rocha-Roa, Valentin Guyard, Dazhi Li, Xinbo Wang, Pietro De Camilli, Stefano Vanni, Karin Reinisch.

In eukaryotes, bridge-like lipid-transfer proteins (BLTPs) are central in mediating vesicle-independent lipid transfer between organelles. BLTPs span the cytosolic space between organelles at contact sites, featuring hydrophobic channels for lipids to travel between membranes. How BLTPs cooperate with partner proteins to orchestrate lipid delivery remains mysterious. Here we used cryo-electron microscopy to visualize a complex comprising the prototypical BLTP VPS13A and the plasma membrane localized scramblase XKR1 at near-atomic resolution. VPS13A interacts with XKR1 via its PH-domain, priming VPS13A's bridge-like lipid-transfer domain to deliver lipids directly to the cytosolic leaflet of the acceptor membrane. In molecular dynamics simulations, such arrangement allows for robust lipid transfer, accelerated by membrane properties. Newly delivered lipids can then be equilibrated between leaflets of the membrane bilayer by the scramblase, allowing for membrane growth. Mechanistic insights regarding lipid delivery by VPS13A are directly applicable to all VPS13 proteins and all BLTP family members more broadly.

DOI: https://doi.org/10.64898/2026.01.07.698282
Mol Biol Cell. 2026 Jan 15. mbcE25080384

A shared binding interface controls Vps13 organelle-specific targeting independently of its vacuolar protein sorting function.

Kevin Ryan Jeffers, Samantha Katarzyna Dziurdzik, Michael Davey, Jordan Faith Drotsky, Elizabeth Conibear.

Yeast vacuolar protein sorting 13 (Vps13) is a bridge-like transporter that directs lipid flow between membranes at organelle contact sites. Vps13 targeting relies on organelle-specific adaptors containing proline-X-proline (PxP) motifs, which compete for binding to the Vps13 adaptor-binding (VAB) domain. Though a VAB-PxP interface has been identified for the mitochondrial adaptor Mcp1, whether other adaptors use identical binding mechanisms is unknown. Moreover, not every Vps13 function is connected to a known PxP adaptor, suggesting other adaptors may exist. Here, we validate the significance of the shared VAB-PxP interface by showing that mutations within this region inhibit both adaptor binding and Vps13 membrane targeting in vivo. Using predictive modeling, we demonstrate that while adaptors share a common Vps13-binding interface, slight differences between these interfaces may contribute to preferential binding and adaptor competition. Notably, we find that the VPS pathway functions independently of the PxP motif binding site. Our results indicate that Vps13 likely employs a non-PxP adaptor mechanism in this pathway, yet the structural integrity of the VAB domain remains essential for proper pathway function.

DOI: https://doi.org/10.1091/mbc.E25-08-0384
Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01581-5. [Epub ahead of print]45(1): 116809

Unveiling the neuroprotective power of mitochondrial transfer in orofacial inflammatory pain through ER membrane remodeling.

Chen Li, Yike Li, Fei Liu, Boyao Lu, Shiyang Ye, Dexin Zhu, Muyun Wang, Junyu Chen, Cheng Zhou, Chunjie Li, Yanyan Zhang, Jiefei Shen.

  Neuro-glial mitochondrial transfer critically sustains neuronal function in disease. While this transfer reshapes inflammatory microenvironments, its pathological mechanisms in peripheral inflammatory pain remain uncharacterized, impeding targeted interventions. Here, employing primary satellite glial cells (SGCs)-trigeminal ganglion neurons (TGNs) co-culture models, we demonstrate that, during acute inflammation, SGCs transfer functional mitochondria to injured TGNs via tunneling nanotubes and free mitochondrial uptake. Inflammatory stress impairs mitophagy, leading to dysfunctional mitochondrial accumulation and heightened neuronal hyperexcitability. Mitochondria from SGCs restore mitophagic flux and enhance mitochondrial-endoplasmic reticulum (ER) contact sites, thereby facilitating calcium exchange and homeostasis while reducing neuronal hyperexcitability. Critically, Atl1 knockout and overexpression mice models reveal that ATL1-driven ER restructuring initiates autophagosome formation during mitophagy and regulates early-stage autophagic progression. Taken together, our findings uncover a neuroprotective axis wherein glial mitochondrial donation safeguards neurons, directly nominating mitochondrial dynamics for therapeutic intervention in orofacial inflammatory pain.

Keywords:  ATL1; CP: cell biology; CP: neuroscience; endoplasmic reticulum; inflammatory pain; mitochondrial transplantation; mitophagy; trigeminal ganglion

DOI:  https://doi.org/10.1016/j.celrep.2025.116809
Stem Cell Res Ther. 2026 Jan 12.

Hypoxia-conditioned BMSC exosomes improve short-term spinal cord injury outcomes via the miR-615-3p/PDE4C-mediated cAMP/PKA pathway.

Wei Bian, Xiangyu Zeng, Ziwen Liu, Mingyan Guan, Tegeleqi Bu, Haoze Li, Zewei Gao, Jianyu Liu.

  Spinal cord injury (SCI) remains a significant global health challenge with limited effective therapeutic options. Exosomes derived from mesenchymal stem cells (MSCs) have emerged as promising neuroprotective agents due to their biocompatibility and immunomodulatory properties. This study investigated the therapeutic potential of hypoxia-conditioned bone marrow MSC (BMSC)-derived exosomes in both in vitro and in vivo SCI models. Hypoxic preconditioning significantly enriched miR-615-3p in bone marrow mesenchymal stem cell (BMSC)-derived exosomes. In spinal neuron injury models, hypoxic exosomes enhanced cell viability, reduced apoptosis, and ameliorated dysfunction of the mitochondria-associated endoplasmic reticulum membranes (MAMs). Mechanistically, miR-615-3p directly targeted and suppressed phosphodiesterase 4 C (PDE4C), activating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. This in turn modulated calcium signaling, attenuated mitochondrial calcium overload, and reduced endoplasmic reticulum stress (ERS). In a mouse model of SCI, short-term treatment with hypoxic exosomes promoted functional recovery within a 14-day post-injury period, as evidenced by improved locomotor performance, reduced lesion volume, attenuated tissue edema, and decreased inflammatory cell infiltration. Furthermore, in vivo administration of hypoxic exosomes upregulated miR-615-3p and downregulated PDE4C expression in injured spinal cord tissues. These results demonstrate that hypoxia-conditioned BMSC-derived exosomes exert neuroprotective effects via the miR-615-3p/PDE4C axis, highlighting their potential as a novel therapeutic strategy for SCI by targeting calcium homeostasis and mitochondrial-ER dysfunction. These findings demonstrate the short-term therapeutic potential of hypoxia-conditioned exosomes in SCI. However, further preclinical studies, including long-term follow-up to assess the durability of recovery and potential late-onset effects, alongside clinical validation, are warranted before clinical translation.

Keywords:  Bone marrow mesenchymal stem cells; Exosomes; Hypoxia conditioning; Neuroprotective effects; Spinal cord injury; miR-615-3p

DOI:  https://doi.org/10.1186/s13287-026-04895-9
Pharmacol Res. 2026 Jan 10. pii: S1043-6618(26)00011-3. [Epub ahead of print]224 108096

Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.

Andrea Mancini, Elisabetta Betterini, Matteo Bordi, Francesco Cecconi.

  Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid-liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion-purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.

Keywords:  Cancer biology; Metabolons; Mitochondria metabolism; Nucleotide metabolism; Organelle contact sites; Purine synthesis

DOI:  https://doi.org/10.1016/j.phrs.2026.108096