bims-mecosi 2025-11-16 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–11–16
thirteen papers selected by
Verena Kohler, Umeå University

A STIMulating new view of activity-dependent membrane contact architecture.
Ist2 promotes lipid transfer by Osh6 via its membrane tethering and lipid scramblase activities.
Mitochondrial-ER crosstalk: An emerging mechanism in the pathophysiology of pulmonary arterial hypertension.
The bridge-like lipid transfer protein Vps13 are required for NVJ integrity and nucleophagy.
Calcium transfer from the ER to other organelles for optimal signaling in Toxoplasma gondii.
Sphingolipid and methionine metabolism in aging.
Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
Interactions between lipid droplets and mitochondria in metabolic diseases.
The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites.
A dynamic feedback loop between retrograde sterol transport and TORC2 controls adaptation of the plasma membrane to stress.
Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.
Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.
Therapeutic remodeling of the ceramide backbone prevents kidney injury.

Trends Cell Biol. 2025 Nov 12. pii: S0962-8924(25)00249-1. [Epub ahead of print]

A STIMulating new view of activity-dependent membrane contact architecture.

Eamonn J Dickson.

  Chhikara et al. reframe stromal interaction molecule (STIM) proteins as structural organizers of membrane contact sites, not just calcium-entry activators, in neurons. STIM2 maintains resting endoplasmic reticulum (ER)-plasma membrane (PM) junctions; STIM1 dynamically expands them during neuronal activity. This activity-dependent remodeling tunes ER-PM proximity and calcium coupling, shifting focus from channel gating to spatial organization.

Keywords:  ER–PM junctions; NMDAR-dependent remodeling; STIM1/STIM2; calcium; dendritic microdomains; store-operated Ca(2+) entry (SOCE)

DOI:  https://doi.org/10.1016/j.tcb.2025.11.001
Sci Adv. 2025 Nov 14. 11(46): eadz2217

Ist2 promotes lipid transfer by Osh6 via its membrane tethering and lipid scramblase activities.

Alicia Fabbre, Camille Syska, Heitor Gobbi Sebinelli, Anna Cardinal, Maud Magdeleine, Noha Al-Qatabi, Juan Martín D'Ambrosio, Cédric Montigny, Guillaume Lenoir, Alenka Čopič, Guillaume Drin.

Lipid transfer proteins unevenly distribute lipids within the cell, which is crucial for its functioning. In yeast, Osh6 transfers phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) by exchange with phosphatidylinositol 4-phosphate. We investigated why its activity depends on Ist2, an ER-resident lipid scramblase that connects the ER to the PM via an intrinsically disordered region (IDR). We found that Osh6, in a lipid-loaded state, binds the Ist2 IDR with micromolar affinity and functions at ER-PM contact sites only if its binding site within the IDR is sufficiently distant from the ER membrane. We determined, in reconstituted contact sites, that the association of Osh6 with the Ist2 IDR enables rapid, directed PS transfer. We identified the Ist2-binding site in Osh6 by molecular modeling and functional analyses. Last, we established that Ist2's scramblase activity sustains Osh6-mediated PS transfer between membranes. Identifying these functional partnerships highlights why lipid transport processes are organized in membrane contact sites.

DOI: https://doi.org/10.1126/sciadv.adz2217
Mitochondrion. 2025 Nov 10. pii: S1567-7249(25)00091-1. [Epub ahead of print] 102094

Mitochondrial-ER crosstalk: An emerging mechanism in the pathophysiology of pulmonary arterial hypertension.

Gauri Chaturvedi, Nandini Dubey, Pranav Panchbhai, Satnam Singh, Ravinder Singh, Upendra Baitha, Neeraj Parakh, Rajiv Narang, Harlokesh Narayan Yadav.

  Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by hyperproliferation and remodeling of the pulmonary vasculature, primarily affecting pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). Although several pharmacological agents target the known signaling pathways in these cells, current therapies fail to reverse vascular remodeling, underscoring the urgent need for novel therapeutic strategies. Recent research has shifted focus towards intracellular organelles, specifically mitochondria and the endoplasmic reticulum (ER), as potential therapeutic targets. A key area of interest is mitochondria-associated membranes (MAMs), specialized contact sites between mitochondria and the ER that regulate essential cellular processes, including calcium homeostasis, ER stress signaling, autophagy, and insulin signaling. This review explores the emerging role of MAMs in the pathogenesis of PAH, detailing the molecular players involved in MAM formation and function. Emphasis is placed on identifying MAM-associated proteins that are dysregulated in PASMCs and PAECs, providing insights into their potential as novel therapeutic targets in PAH.

Keywords:  Novel therapeutic targets; PAECs; PASMCs; Pulmonary arterial hypertension; mitochondria-ER associated membranes

DOI:  https://doi.org/10.1016/j.mito.2025.102094
Biochem Biophys Res Commun. 2025 Nov 06. pii: S0006-291X(25)01648-1. [Epub ahead of print]791 152932

The bridge-like lipid transfer protein Vps13 are required for NVJ integrity and nucleophagy.

Tsuneyuki Takuma, Takashi Ushimaru.

  Bridge-like lipid transfer proteins (BLTPs) constitute a superfamily of proteins localized at various intracellular membrane contact sites (MCSs). Members of this family have been implicated in human neurological disorders. Among them, the BLTP Atg2 is essential for the expansion of isolation membranes in macroautophagy. In this study, we demonstrate that another BLTP, Vps13, is involved in microautophagy in budding yeast. Nucleophagy-the autophagic degradation of nuclear components-is crucial for maintaining nuclear proteostasis, and its dysfunction has been linked to neurodegenerative diseases. In micronucleophagy, a portion of the nucleus is directly engulfed by the vacuolar membrane at the nucleus-vacuole junction (NVJ), followed by degradation within the vacuole. Vps13 accumulates at the NVJ upon inactivation of the target of rapamycin complex 1 (TORC1), a process necessary for NVJ integrity. Vps13 is essential for both micronucleophagy and cell viability under nutrient-deprived conditions. Its localization to the NVJ and lipid transfer activity are both critical for nucleophagy. Taken together, these findings suggest that the bridging and lipid transfer functions of Vps13 are both required for effective nucleophagy. This study uncovers novel physiological roles of Vps13 during starvation.

Keywords:  Autophagy; NVJ; Nucleophagy; TORC1; Vps13; rDNA

DOI:  https://doi.org/10.1016/j.bbrc.2025.152932
Elife. 2025 Nov 12. pii: RP101894. [Epub ahead of print]13

Calcium transfer from the ER to other organelles for optimal signaling in Toxoplasma gondii.

Zhu-Hong Li, Beejan Asady, Le Chang, Myriam Andrea Hortua Triana, Catherine Li, Isabelle Coppens, Silvia N J Moreno.

  Ca2+ signaling in cells begins with the opening of Ca2+ channels in either the plasma membrane (PM) or endoplasmic reticulum (ER), leading to a sharp increase in the physiologically low (<100 nM) cytosolic Ca2+ level. The temporal and spatial regulation of Ca²+ is crucial for the precise activation of key biological processes. In the apicomplexan parasite Toxoplasma gondii, which infects approximately one-third of the global population, Ca²+ signaling governs essential aspects of the parasite's infection cycle. T. gondii relies on Ca²+ signals to regulate pathogenic traits, with several Ca²+-signaling components playing critical roles. Ca2+ entry from the extracellular environment has been demonstrated in T. gondii for both, extracellular parasites, exposed to high Ca2+, and intracellular parasites, which acquire Ca²+ from host cells during host Ca²+ signaling events. Active egress, an essential step of the parasite's infection cycle, is preceded by a large increase in cytosolic Ca2+, most likely initiated by release from intracellular stores. However, extracellular Ca2+ is also necessary to reach a cytosolic Ca2+ threshold required for timely egress. In this study, we investigated the mechanism of intracellular Ca²+ store replenishment and identified a central role for the SERCA-Ca2+-ATPase in maintaining Ca²+ homeostasis within the ER and in other organelles. We demonstrate mitochondrial Ca2+ uptake, which occurs by transfer of Ca2+ from the ER, likely through membrane contact sites. Our findings suggest that the T. gondii ER plays a key role in sequestering and redistributing Ca²+ to intracellular organelles following Ca²+ influx at the PM.

Keywords:  SERCA; Toxoplasma gondii; calcium signaling; cell biology; endoplasmic reticulum; membrane contact sites; mitochondria; toxoplasma gondii

DOI:  https://doi.org/10.7554/eLife.101894
J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):

Sphingolipid and methionine metabolism in aging.

Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.

  Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.

Keywords:  Aging; Metabolism; Methionine; Sphingolipids

DOI:  https://doi.org/10.1242/jcs.264026
Cells. 2025 Oct 23. pii: 1657. [Epub ahead of print]14(21):

Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.

Aya Attia, Katarzyna Majstrowicz, Samruddhi Shembekar, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Martin Bähler.

  Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs.

Keywords:  Miro1/2; Myosin 19; OXPHOS; TRAK; cristae; mitochondria; outer mitochondrial membrane

DOI:  https://doi.org/10.3390/cells14211657
Lipids Health Dis. 2025 Nov 11. 24(1): 357

Interactions between lipid droplets and mitochondria in metabolic diseases.

Guoxin Wang, Bingchan Sun, Huimin Liu, Min Hu, Huan Xu, Hongtao Li, Xijin Wang, Mingfu Tong.

  Metabolic diseases, a major challenge in global public health, are commonly characterized by insulin resistance, lipid metabolism disorders, and mitochondrial dysfunction, and their pathological processes are often accompanied by the abnormal accumulation of lipids in metabolically active tissues such as the liver, heart, and skeletal muscle. Recently, lipid droplets and mitochondria have been shown to interact with each other through membrane contact sites and play a central role in maintaining cellular metabolic homeostasis. The unique monolayer phospholipid membrane structure and formation process of lipid droplets, along with the double-membrane structure and diverse functions of mitochondria, together form the basis for their interaction. There are two modes of interaction, namely dynamic contact and stable anchoring, which are mediated by a variety of proteins to achieve efficient exchange and metabolic regulation of metabolites such as fatty acids. However, dysregulation of lipid droplet-mitochondria interactions initiates a pathogenic cascade involving fatty acid overload, increased reactive oxygen species generation, and mitochondrial dysfunction. These perturbations drive the pathogenesis of metabolic disorders. This review systematically summarizes the key pathological roles of dysregulated lipid droplet-mitochondrial interactions in globally prevalent metabolic diseases such as diabetes mellitus, metabolic dysfunction-associated fatty liver disease, and obesity. This in-depth analysis of molecular mechanisms clarifies the physiological basis of the regulation of lipid homeostasis in the body and provides a theoretical basis for developing novel therapeutic strategies for these diseases to alleviate the related growing global health burden.

Keywords:  Lipid droplets; Lipid droplet‒mitochondria interaction; Membrane contact sites; Metabolic diseases

DOI:  https://doi.org/10.1186/s12944-025-02759-4
Cell Mol Life Sci. 2025 Nov 14. 82(1): 400

The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites.

Kai Jürgens, Lena Menzel, Nora Klinke, Lisa Schäper, Leonhard Breitsprecher, Michael Holtmannspötter, Olympia-Ekaterini Psathaki, Stefan Walter, Sandra Ratnavadivel, Anders Malmendal, Heiko Meyer, Hendrik Milting, Achim Paululat.

  Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC-5) is a fully penetrant form of ARVC caused by the missense mutation in the gene TMEM43p.S358L. Despite extensive research, the molecular basis underlying the detrimental effects of TMEM43p.S358L still needs to be discovered. TMEM43 is a phylogenetically conserved protein. We previously analysed the Drosophila homologue (CG8111 or Dmel\Tmem43) to understand the protein's physiological relevance and the mutation p.S358L. Drosophila Tmem43 is localised at the ER/SR membrane and interacts with the outer mitochondrial membrane protein Porin/VDAC. This interaction is lost in a Tmem43p.S333L mutant that resembles the human p.S358L mutation. In addition, Tmem43p.S333L caused a breakdown in mitochondrial membrane potential and increased cellular reactive oxygen species, suggesting impaired mitochondrial function as a major pathomechanism. Complementary ultrastructural analyses revealed severe structural defects in the affected mitochondria, including degeneration of the organelles. Highly similar ultrastructural defects were observed in the human right ventricular myocardium of a TMEM43p.S358L trait carrier, suggesting a common molecular basis for the detrimental effects of the mutation in flies and humans. We propose that both the p.S358L mutation in humans and the p.S333L mutation in Drosophila impair TMEM43/VDAC interaction, which affects the stability of ER/SR-mitochondrial contact sites and, thus, proper mitochondrial function and oxidative phosphorylation rates. The consequential undersupply of ATP likely results in cardiac cell death and, ultimately, heart failure.

Keywords:  ARVC type 5; Cardiogenesis; Cardiomyopathy; Drosophila model; TMEM43

DOI:  https://doi.org/10.1007/s00018-025-05942-z
EMBO J. 2025 Nov 13.

A dynamic feedback loop between retrograde sterol transport and TORC2 controls adaptation of the plasma membrane to stress.

Maria G Tettamanti, Paulina Nowak, Beata Kusmider, Jennifer M Kefauver, Vincent Mercier, Aurélien Roux, Robbie Loewith.

  Cells monitor and dynamically regulate the lipid composition and biophysical properties of their plasma membrane (PM). The Target Of Rapamycin complex 2 (TORC2) is a protein kinase that acts as a central regulator of plasma membrane homeostasis, but the mechanisms by which it detects and reacts to membrane stresses are poorly understood. To address this knowledge gap, we characterized a family of amphiphilic molecules that physically perturb plasma membrane organization and in doing so inhibit TORC2 in yeast and mammalian cells. Using fluorescent reporters of various lipids in budding yeast, we show that exposure to these small molecules causes mobilization of PM ergosterol as well as inhibition of TORC2. TORC2 inhibition results in activation of the PM-ER sterol transporters Lam2 and Lam4 and the subsequent rapid removal of accessible ergosterol from the plasma membrane via PM-ER contact sites. This sequence of events, culminating in the reactivation of TORC2, is also observed with several other PM stresses, suggesting that TORC2 acts in a feedback loop to control active sterol levels at the plasma membrane to maintain its homeostasis.

Keywords:  Membrane Tension; Plasma Membrane Stress; Small Amphipaths; Sterol Transport; TOR Complex 2

DOI:  https://doi.org/10.1038/s44318-025-00618-7
Cells. 2025 Oct 27. pii: 1678. [Epub ahead of print]14(21):

Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.

Patrice X Petit.

  Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players.

Keywords:  BH3 interacting domain death agonist (also BID-FL); BID; CLOOH; Cell death; DISC; GUV; MTCH2; Mitochondria; Mitochondrial Carrier Homolog 2; OMM outer mitochondrial membrane; cardiolipin peroxidized; death inducing signalling complex; giant unilamellar-vesicles; p15); tBID (truncated BID at the n terminal end

DOI:  https://doi.org/10.3390/cells14211678
Neurochem Res. 2025 Nov 15. 50(6): 361

Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.

Bingjie Han, Jie Bai.

  Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, currently lacks effective treatment options due to its complex pathogenesis. Growing evidence in recent years demonstrates that intracellular Calcium (Ca²⁺) homeostasis disruption plays a critical role in PD development and progression. Ca²⁺ imbalance not only causes Ca²⁺-dependent synaptic dysfunction and impaired neuronal plasticity but also leads to progressive neuronal loss, collectively forming the core pathological characteristics of PD neurodegeneration. Notably, mitochondrial Ca²⁺ imbalance has been identified as a key pathogenic factor in PD. As vital intracellular Ca²⁺ regulators, dysfunctional mitochondria can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), triggering apoptotic cascades. Furthermore, mitochondrial Ca²⁺ overload disrupts oxidative phosphorylation, resulting in excessive reactive oxygen species production that exacerbates neuronal damage. Recent studies reveal the essential role of mitochondria-endoplasmic reticulum interactions in maintaining Ca²⁺ homeostasis, with these organelles forming structurally and functionally integrated connections through mitochondrial ER-associated membrane (MAM) to cooperatively regulate Ca²⁺ ion dynamics. This review describes the molecular mechanisms of mitochondrial Ca²⁺ imbalance in PD pathogenesis and summarizes the potential of mitochondrial channels and MAM-associated proteins as PD therapeutic targets. By thoroughly analyzing these targets mechanisms, we aim to provide a theoretical foundation for developing novel PD treatment strategies based on Ca²⁺ homeostasis regulation. These findings not only expand our understanding of PD pathogenesis but also point toward developing targeted neuroprotective therapies.

Keywords:  Calcium homeostasis; Mitochondria; Mitochondrial endoplasmic reticulum-associated membrane; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11064-025-04591-9
Cell Metab. 2025 Nov 12. pii: S1550-4131(25)00440-1. [Epub ahead of print]

Therapeutic remodeling of the ceramide backbone prevents kidney injury.

Rebekah J Nicholson, Luis Cedeño-Rosario, J Alan Maschek, Trevor Lonergan, Jonathan G Van Vranken, Angela R S Kruse, Chris J Stubben, Liping Wang, Deborah Stuart, Queren A Alcantara, Monica P Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J Clark, Samir Parikh, Jeffrey Spraggins, Donna Romero, Jeremy T Blitzer, Steven P Gygi, Jared Rutter, William L Holland, Nirupama Ramkumar, Scott A Summers.

  Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.

Keywords:  ETC; MICOS; acute kidney injury; ceramides; cristae; lipid metabolism; lipidomics; metabolism; mitochondria; proximal tubule; sphingolipids

DOI:  https://doi.org/10.1016/j.cmet.2025.10.006