bims-mecosi Biomed News
on Membrane contact sites
Issue of 2023‒02‒12
ten papers selected by
Verena Kohler
  1. The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
  2. Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.
  3. Retracted: Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact.
  4. Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
  5. LRRK1 functions as a scaffold for PTP1B-mediated EGFR sorting into ILVs at the ER-endosome contact site.
  6. Mitofusin-2: Functional Switch Between Mitochondrial Function And Neurodegeneration.
  7. ER-PM Junctions on GABAergic Interneurons Are Organized by Neuregulin 2/VAP Interactions and Regulated by NMDA Receptors.
  8. The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
  9. TRPV4 regulates mitochondrial Ca2+-status and physiology in primary murine T cells based on their immunological state.
  10. Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways.
  1. Nat Commun. 2023 Feb 06. 14(1): 638
    The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
    Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman.
      The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.
    DOI:  https://doi.org/10.1038/s41467-023-36298-2
  2. Curr Opin Neurobiol. 2023 Feb 06. pii: S0959-4388(23)00009-0. [Epub ahead of print]79 102684
    Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.
    Robert W Mahley.
      Apolipoprotein (apo) E4 sets the stage for neuropathology in Alzheimer's disease (AD) by causing mitochondrial dysfunction and altering mitochondria-associated membranes. Contact and apposition of mitochondrial-endoplasmic reticulum membranes are enhanced in brain cells in AD and associated with increases in tethering and spacing proteins that modulate many cellular processes. Contact site protein levels are higher in apoE4 cells. In apoE4 neurons, the NAD+/NADH ratio is lowered, reactive oxygen species are increased, and NAD/NADH pathway components and redox proteins are decreased. Oxidative phosphorylation is impaired and reserve ATP generation capacity is lacking. ApoE4 neurons have ∼50% fewer respiratory complex subunits (e.g., ATP synthase) and may increase translocase levels of the outer and inner mitochondrial membranes to facilitate delivery of nucleus-encoded complex subunits. Respiratory complex assembly relies on mitochondrial cristae organizing system subunits that are altered in apoE4 cells, and apoE4 increases mitochondrial proteases that control respiratory subunit composition for complex assembly.
    DOI:  https://doi.org/10.1016/j.conb.2023.102684
  3. Oxid Med Cell Longev. 2023 ;2023 9890809
    Retracted: Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact.
    Oxidative Medicine And Cellular Longevity.
      [This retracts the article DOI: 10.1155/2021/1370862.].
    DOI:  https://doi.org/10.1155/2023/9890809
  4. J Cell Sci. 2023 Feb 06. pii: jcs.260612. [Epub ahead of print]
    Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
    Stephen M Coscia, Cameron P Thompson, Qing Tang, Elana E Baltrusaitis, Joseph A Rhodenhiser, Omar A Quintero-Carmona, E Michael Ostap, Melike Lakadamyali, Erika L F Holzbaur.
      Mitochondrial homeostasis requires a dynamic balance of fission and fusion. The actin cytoskeleton promotes fission; we find that the mitochondrially-localized myosin, Myosin 19 (Myo19), is integral to this process. Myo19 knock-down induces mitochondrial elongation, while Myo19 overexpression induces fragmentation. This mitochondrial fragmentation is blocked by a Myo19 mutation predicted to inhibit ATPase activity and strong actin binding but not by mutations predicted to affect the motor's working stroke that preserve ATPase activity. Super-resolution imaging indicates a dispersed localization of Myo19 on mitochondria, which we find to be dependent on metaxins. These observations suggest that Myo19 acts as a dynamic actin-binding tether that facilitates mitochondrial fragmentation. Myo19-driven fragmentation is blocked by depletion of either the endoplasmic reticulum (ER)-anchored formin INF2-CAAX or the mitochondrially-localized F-actin nucleator Spire1C, which together polymerize actin at sites of mito-ER contact for fission. These observations imply that Myo19 promotes fission by stabilizing mito-ER contacts; we used a split-luciferase system to demonstrate a reduction in these contacts following Myo19 depletion. Our data support a model in which Myo19 tethers mitochondria to ER-associated actin to promote mitochondrial fission.
    Keywords:  Actin; Endoplasmic reticulum; Fission; Mito-ER contacts; Mitochondria; Myosin
    DOI:  https://doi.org/10.1242/jcs.260612
  5. J Cell Sci. 2023 Feb 06. pii: jcs.260566. [Epub ahead of print]
    LRRK1 functions as a scaffold for PTP1B-mediated EGFR sorting into ILVs at the ER-endosome contact site.
    Hiroshi Hanafusa, Keitaro Fujita, Misa Kamio, Shiori Iida, Yasushi Tamura, Naoki Hisamoto, Kunihiro Matsumoto.
      Proper control of epidermal growth factor receptor (EGFR) signaling is important for maintaining cellular homeostasis. Since EGFR signaling occurs at the plasma membrane and endosomes following internalization, endosomal trafficking of EGFR regulates EGFR signaling spatiotemporally. In this process, leucine-rich repeat kinase 1 (LRRK1) has multiple roles in kinase activity-dependent transport of EGFR-containing endosomes and kinase-independent sorting of EGFR into the intraluminal vesicles (ILVs) of multivesicular bodies. Active EGFR inactivates the LRRK1 kinase activity by phosphorylating Tyr-944. In this study, we demonstrate that LRRK1 facilitates EGFR dephosphorylation by PTP1B, an endoplasmic reticulum (ER)-localized protein tyrosine phosphatase, at the ER-endosome contact site, after which EGFR is sorted into the ILVs of endosomes. LRRK1 is required for the PTP1B-EGFR interaction in response to EGF stimulation, resulting in the down-regulation of EGFR signaling. Furthermore, PTP1B activates LRRK1 by dephosphorylating pTyr-944 on the contact site, which promotes the transport of EGFR-containing endosomes. These findings provide evidence that the ER-endosome contact site functions as a hub for LRRK1-dependent signaling that regulates EGFR trafficking.
    Keywords:  EGFR; LRRK1; PTP1B
    DOI:  https://doi.org/10.1242/jcs.260566
  6. Mitochondrion. 2023 Feb 08. pii: S1567-7249(23)00010-7. [Epub ahead of print]
    Mitofusin-2: Functional Switch Between Mitochondrial Function And Neurodegeneration.
    Prakash G Kulkarni, Vaibhavi M Mohire, Pooja K Bhaisa, Mrudula M Joshi, Chitranshi M Puranik, Pranjal P Waghmare, Tanushree Banerjee.
      Mitochondria are highly dynamic organelles known to play role in the regulation of several cellular biological processes. However, their dynamics such as number, shape, and biological functions are regulated by mitochondrial fusion and fission process. The balance between the fusion and fission process is most important for the maintenance of mitochondrial structure as well as cellular functions. The alterations within mitochondrial dynamic processes were found to be associated with the progression of neurodegenerative diseases. In recent years, mitofusin-2 (Mfn2), a GTPase has emerged as a multifunctional protein which not only is found to regulate the mitochondrial fusion-fission process but also known to regulate several cellular functions such as mitochondrial metabolism, cellular biogenesis, signalling, and apoptosis via maintaining the ER-mitochondria contact sites. In this review, we summarize the current knowledge of the structural and functional properties of the Mfn2, its transcriptional regulation and their roles in several cellular functions with a focus on current advances in the pathogenesis of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Mitochondria associated membranes; Mitofusin-2; Neurodegeneration; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.mito.2023.02.001
  7. Int J Mol Sci. 2023 Feb 02. pii: 2908. [Epub ahead of print]24(3):
    ER-PM Junctions on GABAergic Interneurons Are Organized by Neuregulin 2/VAP Interactions and Regulated by NMDA Receptors.
    Detlef Vullhorst, Mara S Bloom, Neha Akella, Andres Buonanno.
      Neuregulins (NRGs) signal via ErbB receptors to regulate neural development, excitability, synaptic and network activity, and behaviors relevant to psychiatric disorders. Bidirectional signaling between NRG2/ErbB4 and NMDA receptors is thought to homeostatically regulate GABAergic interneurons in response to increased excitatory neurotransmission or elevated extracellular glutamate levels. Unprocessed proNRG2 forms discrete clusters on cell bodies and proximal dendrites that colocalize with the potassium channel Kv2.1 at specialized endoplasmic reticulum-plasma membrane (ER-PM) junctions, and NMDA receptor activation triggers rapid dissociation from ER-PM junctions and ectodomain shedding by ADAM10. Here, we elucidate the mechanistic basis of proNRG2 clustering at ER-PM junctions and its regulation by NMDA receptors. Importantly, we demonstrate that proNRG2 promotes the formation of ER-PM junctions by directly binding the ER-resident membrane tether VAP, like Kv2.1. The proNRG2 intracellular domain harbors two non-canonical, low-affinity sites that cooperatively mediate VAP binding. One of these is a cryptic and phosphorylation-dependent VAP binding motif that is dephosphorylated following NMDA receptor activation, thus revealing how excitatory neurotransmission promotes the dissociation of proNRG2 from ER-PM junctions. Therefore, proNRG2 and Kv2.1 can independently function as VAP-dependent organizers of neuronal ER-PM junctions. Based on these and prior studies, we propose that proNRG2 and Kv2.1 serve as co-regulated downstream effectors of NMDA receptors to homeostatically regulate GABAergic interneurons.
    Keywords:  ER-PM junction; FFAT; GABAergic interneuron; Kv2.1; NMDA receptor; VAP; neuregulin 2
    DOI:  https://doi.org/10.3390/ijms24032908
  8. Mol Cells. 2023 Feb 09.
    The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
    Min-Ji Kim, Hoyul Lee, Dipanjan Chanda, Themis Thoudam, Hyeon-Ji Kang, Robert A Harris, In-Kyu Lee.
      Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
    Keywords:  T cell; macrophage; mitochondria quality control; mitochondria-associated membranes; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.14348/molcells.2023.2128
  9. Life Sci. 2023 Feb 08. pii: S0024-3205(23)00127-3. [Epub ahead of print] 121493
    TRPV4 regulates mitochondrial Ca2+-status and physiology in primary murine T cells based on their immunological state.
    Tusar Kanta Acharya, Shamit Kumar, Tejas Pravin Rokade, Young-Tae Chang, Chandan Goswami.
      T cell activation process is critically affected by temperature and intracellular Ca2+-signalling. Yet, the nature and the key molecules involved in such complex Ca2+-signalling is poorly understood. It is mostly assumed that ion channels present in the plasma membrane primarily regulate the cytosolic Ca2+-levels exclusively. TRPV4 is a non-selective Ca2+ channel which can be activated at physiological temperature. TRPV4 is involved in several physiological, pathophysiological process as well as different forms of pain. Here we demonstrate that TRPV4 is endogenously expressed in T cell and is present in the mitochondria of T cells. TRPV4 activation increases mitochondrial Ca2+-levels, and alters mitochondrial temperature as well as specific metabolisms. The TRPV4-dependent increment in the mitochondrial Ca2+ is context-dependent and not just passively due to the increment in the cytosolic Ca2+. Our work also indicates that mitochondrial Ca2+-level correlates positively with a series of essential factors, such as mitochondrial membrane potential, mitochondrial ATP production and negatively correlates with certain factors such as mitochondrial temperature. We propose that TRPV4-mediated mitochondrial Ca2+-signalling and other metabolisms has implications in the immune activation process including immune synapse formation. Our data also endorse the re-evaluation of Ca2+-signalling in T cell, especially in the light of mitochondrial Ca2+-buffering and in higher body temperature, such as in case of fever. Presence of TRPV4 in the mitochondria of T cell is relevant for proper and optimum immune response and may provide evolutionary adaptive benefit. These findings may also have broad implications in different pathophysiological process, neuro-immune cross-talks, and channelopathies involving TRPV4.
    Keywords:  ATP; Ca2+; Cardiolipin; ER-mito contact sites; Membrane potential; Mitochondria; Pain; T cell; TCR activation; TRPV4; Temperature
    DOI:  https://doi.org/10.1016/j.lfs.2023.121493
  10. Front Immunol. 2022 ;13 1051045
    Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways.
    Shiyu Bai, Qielan Wu, Shasha Zhu, Yuwei Zhang, Xuran Chen, Miya Su, Jun Pan, Shuhang Li, Ting Yue, Linfeng Xu, Di Xie, Chenxi Tian, Dan Zhao, Xiang Li, Junjie Hou, Lu Wang, Sicheng Fu, Yanhong Xue, Amin Jiang, Dong Li, Tao Xu, Zhigang Tian, Rongbin Zhou, Huimin Zhang, Li Bai.
      Activation of mTORC1 is essential for anti-tumor function of iNKT cells. The mechanisms underlying impaired mTORC1 activation in intratumoral iNKT cells remain unclear. Via generating Vam6+/- mice and using flow cytometry, image approach, and RNA sequencing, we studied the role of Vam6 in controlling mTORC1 activation and intratumoral iNKT cell functions. Here, we find that increased Vam6 expression in intratumoral iNKT cells leads to impaired mTORC1 activation and IFN-γ production. Mechanistically, Vam6 in iNKT cells is essential for Rab7a-Vam6-AMPK complex formation and thus for recruitment of AMPK to lysosome to activate AMPK, a negative regulator of mTORC1. Additionally, Vam6 relieves inhibitory effect of VDAC1 on Rab7a-Vam6-AMPK complex formation at mitochondria-lysosome contact site. Moreover, we report that lactic acid produced by tumor cells increases Vam6 expression in iNKT cells. Given the key roles of increased Vam6 in promoting AMPK activation in intratumoral iNKT cells, reducing Vam6 expression signifificantly enhances the mTORC1 activation in intratumoral iNKT cells as well as their anti-tumor effificacy. Together, we propose Vam6 as a target for iNKT cell-based immunotherapy.
    Keywords:  AMPK; Rab7a-Vam6-AMPK complex; Vam6; iNKT cells; mTORC1
    DOI:  https://doi.org/10.3389/fimmu.2022.1051045
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒30 at 8:22.