bims-mecosi 2023-05-14 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2023–05–14
eight papers selected by
Verena Kohler, University of Graz

Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways.
The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders.
In situ architecture of the ER-mitochondria encounter structure.
Vps13 is required for efficient autophagy in Saccharomyces cerevisiae.
Membrane contact sites orchestrate cholesterol homeostasis that is central to vascular aging.
Effect of rapamycin on lysosomal accumulation in a CRISPR/Cas9-based cellular model of VPS13A deficiency.
Sec16 and Sed4 interdependently function as interaction and localization partners at ER exit sites.
Structure and function of lipid droplet assembly complexes.

Ageing Res Rev. 2023 May 08. pii: S1568-1637(23)00110-1. [Epub ahead of print] 101951

Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways.

Hongzheng Wu, Wanxin Chen, Zhenni Chen, Xianping Li, Min Wang.

  Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between endoplasmic reticulum (ER), the main intracellular calcium storage organelles, and mitochondria has been recognized for decades, and its main roles in the ion and lipid transport, ROS signaling, membrane dynamic changes and cellular metabolism are basically determined. At present, many tumor chemotherapeutic drugs rely on ER- mitochondrial calcium signal to function, but the mechanism of targeting resident molecules at the mitochondria-associated endoplasmic reticulum membranes (MAM) to sensitize traditional chemotherapy and the new tumor therapeutic targets identified based on the signal pathways on the MAM have not been thoroughly discussed. In this review, we highlight the key roles of various signaling pathways at ER-mitochondria contact in tumorigenesis and focus on novel anticancer therapy strategies targeting potential targets at this contact site.

Keywords:  Cancer; MAM; Therapeutic; targets

DOI:  https://doi.org/10.1016/j.arr.2023.101951
J Cell Biochem. 2023 May 09.

The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders.

Saeid Bagheri-Mohammadi, Mohammad Farjami, Ali Jaafari Suha, Seyed Mohsen Aghaei Zarch, Sajad Najafi, Ali Esmaeili.

  Mitochondrial calcium (Ca2+ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca2+ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca2+ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca2+ signaling at the molecular level. The biological function of Ca2+ channels and transporters as well as the role of mitochondrial Ca2+ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca2+ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca2+ homeostasis and also mitochondrial functions have expanded the number of targeted treatments. The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.

Keywords:  Alzheimer's disease; ageing; calcium signaling; cellular homeostasis; mitochondria-associated ER membrane; therapeutic strategy

DOI:  https://doi.org/10.1002/jcb.30414
Nature. 2023 May 10.

In situ architecture of the ER-mitochondria encounter structure.

Michael R Wozny, Andrea Di Luca, Dustin R Morado, Andrea Picco, Rasha Khaddaj, Pablo Campomanes, Lazar Ivanović, Patrick C Hoffmann, Elizabeth A Miller, Stefano Vanni, Wanda Kukulski.

The endoplasmic reticulum and mitochondria are main hubs of eukaryotic membrane biogenesis that rely on lipid exchange via membrane contact sites1-3, but the underpinning mechanisms remain poorly understood. In yeast, tethering and lipid transfer between the two organelles is mediated by the endoplasmic reticulum-mitochondria encounter structure (ERMES), a four-subunit complex of unresolved stoichiometry and architecture4-6. Here we determined the molecular organization of ERMES within Saccharomyces cerevisiae cells using integrative structural biology by combining quantitative live imaging, cryo-correlative microscopy, subtomogram averaging and molecular modelling. We found that ERMES assembles into approximately 25 discrete bridge-like complexes distributed irregularly across a contact site. Each bridge consists of three synaptotagmin-like mitochondrial lipid binding protein domains oriented in a zig-zag arrangement. Our molecular model of ERMES reveals a pathway for lipids. These findings resolve the in situ supramolecular architecture of a major inter-organelle lipid transfer machinery and provide a basis for the mechanistic understanding of lipid fluxes in eukaryotic cells.

DOI: https://doi.org/10.1038/s41586-023-06050-3
Contact (Thousand Oaks). 2022 Jan-Dec;5:5

Vps13 is required for efficient autophagy in Saccharomyces cerevisiae.

Yuchen Lei, Xin Wen, Daniel J Klionsky.

  Vps13 is a large, conserved protein that transports lipids between membranes. Its localization at multiple organelle membranes and membrane contact sites suggests its important physiological roles. In addition, the high correlation of mutant VPS13 with certain diseases, especially those involving neurodegeneration, makes this protein of considerable biomedical interest. Taking advantage of the fact that yeasts only have one Vps13 protein, the roles of yeast Vps13 have been well studied. However, whether and how Vps13 functions in macroautophagy/autophagy, a process of degradation of cytoplasmic cargoes, have been elusive questions. In this paper, we investigated the role of Vps13 in both non-selective and selective autophagy and found that this protein participates in non-selective autophagy, reticulophagy and pexophagy, but not mitophagy, and that Vps13 plays a role in the late stage of autophagy.

Keywords:  Membrane; mitophagy; protein trafficking; stress; vacuole

DOI:  https://doi.org/10.1177/25152564221136388
WIREs Mech Dis. 2023 May 08. e1612

Membrane contact sites orchestrate cholesterol homeostasis that is central to vascular aging.

Wenjing Li, Yiyun Pang, Kehan Jin, Yuru Wang, Yujie Wu, Jichang Luo, Wenlong Xu, Xiao Zhang, Ran Xu, Tao Wang, Liqun Jiao.

  Chronological age causes structural and functional vascular deterioration and is a well-established risk factor for the development of cardiovascular diseases, leading to more than 40% of all deaths in the elderly. The etiology of vascular aging is complex; a significant impact arises from impaired cholesterol homeostasis. Cholesterol level is balanced through synthesis, uptake, transport, and esterification, the processes executed by multiple organelles. Moreover, organelles responsible for cholesterol homeostasis are spatially and functionally coordinated instead of isolated by forming the membrane contact sites. Membrane contact, mediated by specific protein-protein interaction, pulls opposing organelles together and creates the hybrid place for cholesterol transfer and further signaling. The membrane contact-dependent cholesterol transfer, together with the vesicular transport, maintains cholesterol homeostasis and has intimate implications in a growing list of diseases, including vascular aging-related diseases. Here, we summarized the latest advances regarding cholesterol homeostasis by highlighting the membrane contact-based regulatory mechanism. We also describe the downstream signaling under cholesterol homeostasis perturbations, prominently in cholesterol-rich conditions, stimulating age-dependent organelle dysfunction and vascular aging. Finally, we discuss potential cholesterol-targeting strategies for therapists regarding vascular aging-related diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology.

Keywords:  cardiovascular diseases; cellular organelles; cholesterol; membrane contact sites; vascular aging

DOI:  https://doi.org/10.1002/wsbm.1612
J Cell Mol Med. 2023 May 10.

Effect of rapamycin on lysosomal accumulation in a CRISPR/Cas9-based cellular model of VPS13A deficiency.

A R Tornero-Écija, M A Navas, S Muñoz-Braceras, O Vincent, R Escalante.

  VPS13A is a lipid transfer protein localized at different membrane contact sites between organelles, and mutations in the corresponding gene produce a rare neurodegenerative disease called chorea-acanthocytosis (ChAc). Previous studies showed that VPS13A depletion in HeLa cells results in an accumulation of endosomal and lysosomal markers, suggesting a defect in lysosomal degradation capacity leading to partial autophagic dysfunction. Our goal was to determine whether compounds that modulate the endo-lysosomal pathway could be beneficial in the treatment of ChAc. To test this hypothesis, we first generated a KO model using CRISPR/Cas9 to study the consequences of the absence of VPS13A in HeLa cells. We found that inactivation of VPS13A impairs cell growth, which precludes the use of isolated clones due to the undesirable selection of edited clones with residual protein expression. Therefore, we optimized the use of pool cells obtained shortly after transfection with CRISPR/Cas9 components. These cells are a mixture of wild-type and edited cells that allow a comparative analysis of phenotypes and avoids the selection of clones with residual level of VPS13A expression after long-term growth. Consistent with previous observations by siRNA inactivation, VPS13A inactivation by CRISPR/Cas9 resulted in accumulation of the endo-lysosomal markers RAB7A and LAMP1. Notably, we observed that rapamycin partially suppressed the difference in lysosome accumulation between VPS13A KO and WT cells, suggesting that modulation of the autophagic and lysosomal pathway could be a therapeutic target in the treatment of ChAc.

Keywords:  CRISPR/Cas9; VPS13A; autophagy; chorea-acanthocytosis; rapamycin

DOI:  https://doi.org/10.1111/jcmm.17768
J Cell Sci. 2023 May 01. pii: jcs261094. [Epub ahead of print]136(9):

Sec16 and Sed4 interdependently function as interaction and localization partners at ER exit sites.

Tomohiro Yorimitsu, Ken Sato.

  COPII proteins assemble at ER exit sites (ERES) to form transport carriers. The initiation of COPII assembly in the yeast Saccharomyces cerevisiae is triggered by the ER membrane protein Sec12. Sec16, which plays a critical role in COPII organization, localizes to ERES independently of Sec12. However, the mechanism underlying Sec16 localization is poorly understood. Here, we show that a Sec12 homolog, Sed4, is concentrated at ERES and mediates ERES localization of Sec16. We found that the interaction between Sec16 and Sed4 ensures their correct localization to ERES. Loss of the interaction with Sec16 leads to redistribution of Sed4 from the ERES specifically to high-curvature ER areas, such as the tubules and edges of the sheets. The luminal domain of Sed4 mediates this distribution, which is required for Sed4, but not for Sec16, to be concentrated at ERES. We further show that the luminal domain and its O-mannosylation are involved in the self-interaction of Sed4. Our findings provide insight into how Sec16 and Sed4 function interdependently at ERES.

Keywords:  COPII; ER; ER exit sites; Endoplasmic reticulum; Sec16; Sed4

DOI:  https://doi.org/10.1242/jcs.261094
Curr Opin Struct Biol. 2023 May 05. pii: S0959-440X(23)00080-5. [Epub ahead of print]80 102606

Structure and function of lipid droplet assembly complexes.

Tobias C Walther, Siyoung Kim, Henning Arlt, Gregory A Voth, Robert V Farese.

  Cells store lipids as a reservoir of metabolic energy and membrane component precursors in organelles called lipid droplets (LDs). LD formation occurs in the endoplasmic reticulum (ER) at LD assembly complexes (LDAC), consisting of an oligomeric core of seipin and accessory proteins. LDACs determine the sites of LD formation and are required for this process to occur normally. Seipin oligomers form a cage-like structure in the membrane that may serve to facilitate the phase transition of neutral lipids in the membrane to form an oil droplet within the LDAC. Modeling suggests that, as the LD grows, seipin anchors it to the ER bilayer and conformational shifts of seipin transmembrane segments open the LDAC dome toward the cytoplasm, enabling the emerging LD to egress from the ER.

Keywords:  Endoplasmic reticulum; Lipid droplet; Phase separation; Phospholipids; Seipin; Sterol esters; Surface tension; Triacylglycerol

DOI:  https://doi.org/10.1016/j.sbi.2023.102606