bims-mecosi 2026-04-12 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–04–12
eight papers selected by
Verena Kohler, Umeå University

Organelle contact sites in cancer cells.
The molecular basis of tricalbin-mediated membrane contact site organization in cells.
Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
ER-Mitochondria Tethering and Calcium Flux: A Core Mechanism for Biomineralization.
TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease.
Endoplasmic reticulum architecture in liver metabolic regulation.
Membrane integrity control - from lipids to proteins and back to lipids.
A modular design of two-pronged sub-organelle targeting strategy disrupting mitochondria-endoplasmic reticulum crosstalk for mitigating rheumatoid arthritis.

Cell Death Dis. 2026 Apr 04.

Organelle contact sites in cancer cells.

Ilaria Celotti, Matteo Scavezzon, Sabrina Toffanin, Alessia Ruzza, Federica Vianello, Elisabetta Zaltron, Carol Bastianello, Michela Rossini, Filippo Severin, Luigi Leanza.

Membrane contact sites (MCSs) are defined as regions of functional proximity between membranes belonging to the same or different organelle types. These interactions are mediated by specialised proteins promoting the formation of these crosstalk hubs. Previously, organelles were considered to act independently in cellular physiology. However, it is now evident they carry out specific functions at MCSs. The first interactions described involved endoplasmic reticulum and mitochondria. Subsequently, many contacts involving different organelles emerged. MCSs affect several cellular processes, including intracellular signalling, lipid and ion homeostasis, transport of molecules, cellular metabolism, and redox balance. Disruption of these interactions has been described to be associated with various pathologies, including cancer. While the role of MCSs in tumours remains unclear, recent findings suggest they may influence cancer progression, so, in the near future, modulating organelle interactions could provide novel therapeutic options and develop new protocol to treat tumours.Schematic overview of intracellular MCSs, their effects on biological processes and the associated cancer-related outcomes. MCSs involve different cellular organelles allowing their intercommunication, finally participating in a plethora of cellular processes ranking from calcium and ions exchange, lipid transport and regulation of cell survival. Thus, MCSs modulation has been demonstrated to play a pivotal role in the modulation of cancer aggressiveness.

DOI: https://doi.org/10.1038/s41419-026-08674-5
J Cell Sci. 2026 Apr 08. pii: jcs.264421. [Epub ahead of print]

The molecular basis of tricalbin-mediated membrane contact site organization in cells.

Lazar Ivanović, Anne-Laure Boinet, Andrea Picco, Eliane Zinn, Daniela Ross-Kaschitza, Marko Kaksonen, Wanda Kukulski.

  Membrane contact sites facilitate molecular exchanges through physical interactions between organelles, connected by specific protein tethers. Among these tethers are the tricalbins, which mediate contacts between endoplasmic reticulum (ER) and plasma membrane in yeast. Tricalbins are integral to the ER, have a cytosolic lipid binding domain and bind the plasma membrane through C2 domains. Here, we combine fluorescence recovery after photobleaching with correlative light and 3D electron microscopy to dissect how tricalbins control their localization, dynamic distribution and contact site organization. We find that heteromerization via lipid binding domains is a prerequisite for tricalbin accumulation at contact sites, membrane curvature sensing and restrained mobility in the ER. By altering tricalbin protein domains, we show that intermembrane distances and intrinsically disordered regions interdependently control distribution and dynamics of contact site tethers. Our study reveals principles of contact site architecture that are fine-tuned by tricalbin domain organization.

Keywords:  Correlative light and electron microscopy; FRAP; Live imaging; Membrane contact sites; Tricalbins; Yeast

DOI:  https://doi.org/10.1242/jcs.264421
Ageing Res Rev. 2026 Apr 07. pii: S1568-1637(26)00123-6. [Epub ahead of print] 103131

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

Linbo Peng, Kexin Wang, Limin Wu, Lei Yao, Bin Shen, Jian Li.

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

Keywords:  Calcium homeostasis; Degenerative musculoskeletal diseases; ER–mitochondria crosstalk; Mitochondria-associated ER membranes; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.arr.2026.103131
FASEB J. 2026 Apr 15. 40(7): e71751

ER-Mitochondria Tethering and Calcium Flux: A Core Mechanism for Biomineralization.

Xinyi Zhou, Mengge Feng, Zhe Li, Tian Gan, Yuxuan Zhang, Xiaoxin Ma, Ruoyi Wu, Yunyun Xie, Fangfang Song, Guobin Yang, Yufeng Zhang.

  Biomineralization refers to the process by which organisms form inorganic minerals, predominantly through the deposition of calcium phosphates. Calcium ions (Ca2+) serve not only as a fundamental component of the mineral phase but also as key signaling messengers that actively regulate the efficiency and progression of this process. The endoplasmic reticulum (ER) and mitochondria are two major organelles responsible for calcium ion storage and regulation within cells. Contact sites between mitochondria and ER, also called mitochondria-ER contacts (MERCs) or mitochondria-associated ER membranes (MAMs), have been identified as vital spots for calcium transfer. Existing research indicates that calcium ion transport from the ER to mitochondria occupies a pivotal position in biomineralization, but the relevance of MERC integrity in biomineralization is yet to be determined. This study revealed increased MERCs and calcium ion transport during mineralization in vivo and in vitro. Additionally, significantly impaired endoplasmic reticulum-mitochondrial interactions were observed in bone marrow mesenchymal stem cells (BMSCs) from ovariectomy-induced osteoporotic mice. Experimental enhancement of MERCs effectively increased mineralized nodule formation and alleviated ovariectomy-induced osteoporosis, whereas disruption of MERC integrity inhibited mineralization. Our findings indicate that endoplasmic reticulum-mitochondrial calcium ion transport plays a crucial role in biomineralization. This discovery provides a stronger theoretical foundation for elucidating the biomineralization process and may also identify novel therapeutic targets for related diseases.

Keywords:  biomineralization; calcium transport; endoplasmic reticulum (ER); mitochondria; mitochondria‐ER contacts (MERCs); mitochondria‐associated ER membranes (MAMs); osteoporosis

DOI:  https://doi.org/10.1096/fj.202504909R
Alzheimers Dement. 2026 Apr;22(4): e71306

TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease.

Neil V Yang, Shaowei Wang, Boyang Li, Jeffrey Simms, Linsey Dinh, Annie Huang, Jacob H Oei, Hussein N Yassine, Ronald M Krauss.

   INTRODUCTION: While the apolipoprotein E (APOE) ε4 allele is a major risk factor for Alzheimer's disease (AD), the role of translocase of outer mitochondrial membrane 40 (TOMM40)-an adjacent gene involved in mitochondrial protein import-is not known.
METHODS: Human brain tissue, human induced pluripotent stem cell-derived neurons (iNeurons), and mice were used for study of gene expression, cholesterol metabolism, mitochondrial function, and animal cognition.
RESULTS: Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. In human iNeurons, TOMM40 knockdown (KD) disrupted mitochondria-endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of liver X receptor beta (NR1H2), upregulation of APOE and low-density lipoprotein receptor (LDLR), and increased cellular cholesterol and amyloid beta (Aβ)42 independent of APOE ε4. Consistently, Tomm40 KD in mice induced increased brain cholesterol, Aβ42 content, and impaired memory.
DISCUSSION: TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function.

Keywords:  Alzheimer's disease; apolipoprotein E; cholesterol metabolism; mitochondria; mitochondria–endoplasmic reticulum contact sites; translocase of outer mitochondrial membrane 40

DOI:  https://doi.org/10.1002/alz.71306
Trends Cell Biol. 2026 Apr 07. pii: S0962-8924(26)00035-8. [Epub ahead of print]

Endoplasmic reticulum architecture in liver metabolic regulation.

Leonardo Luis Artico, Sophia Hakam, Güneş Parlakgül, Ana Paula Arruda.

  The endoplasmic reticulum (ER) is a central hub for essential cellular processes, including lipid and glucose metabolism, protein folding, calcium homeostasis, and detoxification. The ER exhibits a complex architecture, comprising multiple subdomains such as the nuclear envelope and the peripheral ER, which is further organized into sheets, tubules, three-way junctions, and contact sites. Both ER form and function are highly adaptive, with a robust capacity to respond to changes in environmental cues such as nutritional states. Here, we discuss remodeling of ER shape - as a fundamental mechanism of metabolic regulation, which enables the diversification and fine-tuning of metabolic function in physiology, while also representing a potential point of vulnerability during metabolic stress. We focus on the liver, a central organ in systemic energy homeostasis, and examine how hepatic ER morphology and its dynamic interorganelle interactions are reorganized in response to nutritional fluctuations and how this remodeling reflects on metabolic function.

Keywords:  endoplasmic reticulum; hepatocytes; lipids; liver; metabolism; organelle contacts

DOI:  https://doi.org/10.1016/j.tcb.2026.03.004
J Cell Sci. 2026 Apr 01. pii: jcs264503. [Epub ahead of print]139(7):

Membrane integrity control - from lipids to proteins and back to lipids.

Baicong Mu, Dan Zhang.

  Membrane integrity is vital for cell survival and function. Despite constant mechanical and chemical challenges, cellular membranes exhibit remarkable resilience through highly coordinated protective and repair mechanisms. Here, we outline a mechanistic framework in which biological membranes function as dynamic mechano-chemical integrators, linking lipid physicochemical properties with protein-mediated stress responses and Ca2+ signaling to maintain membrane integrity. We further discuss how intrinsic bilayer features give rise to both distinct and shared strategies that safeguard membrane homeostasis. We also highlight the emerging roles of lipid transporters and biomolecular condensates in membrane stress surveillance and repair. Collectively, we propose that lipid-protein-lipid feedback loops, in which membrane perturbations activate protein effectors that remodel bilayer composition or organization, form robust circuits enabling rapid sensing, signal amplification, and membrane adaptation and repair, thereby preserving membrane integrity under fluctuating stress conditions.

Keywords:  Biomolecular condensates; Calcium signaling; Lipid transfer protein; Membrane biophysics; Membrane contact sites; Membrane integrity; Membrane repair; Non-vesicular lipid transfer

DOI:  https://doi.org/10.1242/jcs.264503
Biomaterials. 2026 Apr 06. pii: S0142-9612(26)00236-X. [Epub ahead of print]333 124212

A modular design of two-pronged sub-organelle targeting strategy disrupting mitochondria-endoplasmic reticulum crosstalk for mitigating rheumatoid arthritis.

Jianheng Ren, Yao Tang, Zhumei Liao, Xin Wen, Yuanyi Hua, Yan Li, Qin Wang.

  The pathological crosstalk between endoplasmic reticulum (ER) stress and mitochondria (MT) dysfunction aggravates rheumatoid arthritis (RA) process by promoting the abnormal formation of mitochondria-associated ER membranes (MAMs). Current single organelle-specific therapies are insufficient to halt MAMs-mediated pathological inter-organelle communication and thereby showed limited efficacy in suppressing RA. A two-pronged dual organelles regulatory strategy that concurrently inhibit ER stress and MT dysfunction, thereby suppressing the aberrant MAMs formation will be promising to achieve prolonged RA remission. Due to the multiple delivery barriers from tissue to sub-organelle level, conventional approaches involve decorating nanocarriers with multiple functional groups. However, this typically leads to increased structural complexity and unpredictable in vivo performance. Here, we adopted a minimalist modular design strategy. By fine-tuning the density and ratio of dual organelles-targeted modules, we optimized the physicochemical properties of the Res@DPGT nanoplatform for maximal sub-organelle drug delivery. The optimal two-pronged nanoplatform Res@DPGT achieve a hierarchical targeting process from the tissue level to sub-organelle level, ultimately delivering therapeutic resveratrol (Res) to ER and MT. In inflammatory cells, Res@DPGT significantly suppress ER stress and MT dysfunction by disrupting MAMs formation, eliciting potent anti-inflammatory efficacy. In arthritic rats, intravenously administrated Res@DPGT show enhanced internalization by circulating monocytes and leverage the inflammatory tropism of circulating monocytes to achieve preferential distribution and prolonged retention in inflamed joints. Ultimately, Res@DPGT remarkedly alleviate RA by disrupting the MAMs-mediated pathological ER-MT coupling.

Keywords:  Inflammation-targeted delivery; Mitochondrial-associated endoplasmic reticulum membranes (MAMs); Rheumatoid arthritis; Sub-organelle targeting; Two-pronged strategy

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124212