bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–05–11
six papers selected by
Verena Kohler, Umeå University
  1. Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.
  2. Dimethyl Fumarate Improves Non-Alcoholic Fatty Liver Disease by Regulating SIRT1 Signal to Inhibit MAMs Over-Enrichment.
  3. Depletion of oxysterol-binding proteins by OSW-1 triggers RIP1/RIP3-independent necroptosis and sensitization to cancer immunotherapy.
  4. A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.
  5. ER-PM tether Syt1 limits cell-to-cell connectivity via plasmodesmata during innate immune responses in Arabidopsis.
  6. Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
  1. Bioessays. 2025 May 04. e70016
    Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.
    Seiji Watanabe, Koji Yamanaka.
      Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca2+ transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.
    Keywords:  mitochondria‐associated membranes; neurodegenerative diseases; protein homeostasis
    DOI:  https://doi.org/10.1002/bies.70016
  2. Eur J Pharmacol. 2025 May 06. pii: S0014-2999(25)00447-9. [Epub ahead of print] 177693
    Dimethyl Fumarate Improves Non-Alcoholic Fatty Liver Disease by Regulating SIRT1 Signal to Inhibit MAMs Over-Enrichment.
    Rui Zhang, Quanwei Zhang, ZiYi Cui, BenZeng Huang, Yulei Wang, Haitian Ma.
      Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder of the liver with an increasing global prevalence. Despite significant advancements in understanding NAFLD, effective therapeutic strategies remain limited. Mitochondria-associated membranes (MAMs) are specialized domains of the endoplasmic reticulum (ER) that closely interact with mitochondria and play a crucial role in regulating Ca2+ homeostasis. Our previous research demonstrated that dimethyl fumarate (DMF) alleviates NAFLD by modulating hepatic Ca2+ homeostasis. However, the precise mechanisms remain unclear. In this study, we found that DMF significantly alleviated lipid accumulation in NAFLD mice by inhibiting excessive MAMs enrichment. Mechanistically, DMF improved mitochondrial function by reducing mitochondrial Ca2+ overload and oxidative stress caused by MAMs over-enrichment. Furthermore, our results demonstrated that protective effects of DMF against NAFLD are dependent on Sirtuin-1 (SIRT1) regulation. Inhibition of SIRT1 markedly reversed the ability of DMF to suppress MAMs over-enrichment in both in vitro and in vivo models. Moreover, the beneficial effects of DMF on oxidative stress, mitochondrial dysfunction, and hepatic steatosis were abrogated by co-administration of EX527, a selective SIRT1 inhibitor. In summary, our findings demonstrate that DMF alleviates mitochondrial Ca2+ dysregulation caused by aberrant MAMs enrichment, thereby reducing oxidative stress and mitochondrial dysfunction, ultimately inhibiting lipid accumulation in hepatocytes. These results provide new insights into the therapeutic potential of DMF for NAFLD treatment.
    Keywords:  Dimethyl fumarate; Fatty liver disease; Mitochondria Ca(2+) overload; Mitochondria associated membrane (MAMs); SIRT1signal
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177693
  3. Cell Death Differ. 2025 May 06.
    Depletion of oxysterol-binding proteins by OSW-1 triggers RIP1/RIP3-independent necroptosis and sensitization to cancer immunotherapy.
    Xinyan Lu, Dongshi Chen, Min Wang, Xiangping Song, Kaylee Ermine, Suisui Hao, Anupma Jha, Yixian Huang, Ying Kang, Haibo Qiu, Heinz-Josef Lenz, Song Li, Zhendong Jin, Jian Yu, Lin Zhang.
      Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.
    DOI:  https://doi.org/10.1038/s41418-025-01521-8
  4. J Cell Sci. 2025 May 01. pii: jcs263907. [Epub ahead of print]138(9):
    A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.
    Thomas Simmen, Luca Pellegrini.
      Mitochondrial cholesterol biology in non-steroidogenic tissues remains understudied in cell science. Although detecting cholesterol in mitochondria is challenging due to isolation difficulties, studies using mitoplasts (mitochondria stripped of their outer membrane) and imaging approaches confirm its presence in the inner mitochondrial membrane. Through analysis of published evidence and first-principles reasoning, we advance a model of cholesterol trafficking into and out of mitochondria via phospholipids at mitochondria-associated membranes (MAMs), challenging the traditional view of protein-driven transport. In this model, cholesterol enters mitochondria alongside phosphatidylserine and exits with phosphatidylethanolamine - either unchanged or in a hydroxylated form after modification by the enzyme CYP27A1. Strong cholesterol-phospholipid binding energies, ∼17 kcal/mol (71.128 kJ/mol), support this lipid-mediated mechanism, suggesting it complements protein-based pathways. Future research should explore how these mechanisms collaborate to regulate mitochondrial cholesterol trafficking. By rethinking cholesterol dynamics, we raise the possibility that cholesterol plays a larger role in mitochondrial biology, influencing membrane-dependent functions like cristae structure, respiratory efficiency and inter-organelle communication. This Perspective also highlights the potential of mitochondria to regulate both dietary and endogenous cholesterol flux and homeostasis across the cell.
    Keywords:  Lipid biology; Membrane trafficking; Organelles
    DOI:  https://doi.org/10.1242/jcs.263907
  5. Cell Rep. 2025 May 03. pii: S2211-1247(25)00443-7. [Epub ahead of print]44(5): 115672
    ER-PM tether Syt1 limits cell-to-cell connectivity via plasmodesmata during innate immune responses in Arabidopsis.
    Jiajing Li, Pengfei Lu, Qing Pan, Bingxiao Wang, Youjun Wang, Jiejie Li.
      Upon perception of microbe-associated molecular patterns (MAMPs), plants close plasmodesmata (PD) as part of their innate immune responses. However, the signaling cascades and molecular mechanisms underlying MAMP-induced PD closure require further investigation. Here, we show that the endoplasmic reticulum (ER)-plasma membrane (PM) tether Synaptotagmin 1 (Syt1) modulates the response of PD to MAMPs. Following MAMP stimulation, Syt1 rapidly accumulates to PD and further recruits a putative calcium-permeable transporter, ANN4, to promote a localized, PD-associated Ca2+ elevation, leading to callose-dependent PD closure. Moreover, Syt1 can sense the increased level of PI(4,5)P2 at the PD-PM via its C2 domain. Disrupting the interaction between Syt1 and PM lipids by pharmaceutical approaches or site-directed mutagenesis leads to impaired PD response to MAMPs. Collectively, our findings reveal that Syt1 integrates phospholipid signaling from the PD-PM to regulate PD-localized Ca2+ elevation, thereby modulating intercellular communication for restricting the spread of bacterial infection.
    Keywords:  CP: Cell biology; CP: Plants; ER-PM contact sites; plant innate immunity; plasmodesmata; symplasmic trafficking; synaptotagmin
    DOI:  https://doi.org/10.1016/j.celrep.2025.115672
  6. EMBO J. 2025 May 09.
    Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
    Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier.
      Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.
    Keywords:  Annexin-A5; Apoptotic Cell Death; Intermembrane Space Ca2⁺ Signaling; VDAC1 Ca2+ Permeability
    DOI:  https://doi.org/10.1038/s44318-025-00454-9
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