bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024–01–28
eight papers selected by
Verena Kohler, Umeå University
  1. Functional interplay of lipid droplets and mitochondria.
  2. Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.
  3. The peroxisome: an update on mysteries 3.0.
  4. Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging.
  5. The SIRT3-ATAD3A axis regulates MAM dynamics and mitochondrial calcium homeostasis in cardiac hypertrophy.
  6. The Endoplasmic Reticulum-Plasma Membrane Tethering Protein Ice2 Controls Lipid Droplet Size via the Regulation of Phosphatidylcholine in Candida albicans.
  7. The role of ATP-binding cassette transporter G1 (ABCG1) in Alzheimer's disease: A review of the mechanisms.
  8. Mapping of cytosol-facing organelle outer membrane proximity proteome by proximity-dependent biotinylation in living Arabidopsis cells.
  1. FEBS Lett. 2024 Jan 24.
    Functional interplay of lipid droplets and mitochondria.
    Ludovic Enkler, Anne Spang.
      Our body stores energy mostly in form of fatty acids (FAs) in lipid droplets (LDs). From there the FAs can be mobilized and transferred to peroxisomes and mitochondria. This transfer is dependent on close opposition of LDs and mitochondria and peroxisomes and happens at membrane contact sites. However, the composition and the dynamics of these contact sites is not well understood, which is in part due to the dependence on the metabolic state of the cell and on the cell- and tissue-type. Here, we summarize the current knowledge on the contacts between lipid droplets and mitochondria both in mammals and in the yeast Saccharomyces cerevisiae, in which various contact sites are well studied. We discuss possible functions of the contact site and their implication in disease.
    Keywords:  disease; fatty acids; mammals; metabolism; stress; yeast; β-oxidation
    DOI:  https://doi.org/10.1002/1873-3468.14809
  2. Nature. 2024 Jan 24.
    Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.
    Christopher J Obara, Jonathon Nixon-Abell, Andrew S Moore, Federica Riccio, David P Hoffman, Gleb Shtengel, C Shan Xu, Kathy Schaefer, H Amalia Pasolli, Jean-Baptiste Masson, Harald F Hess, Christopher P Calderon, Craig Blackstone, Jennifer Lippincott-Schwartz.
      To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites1,2. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites3,4. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle5,6. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation7,8, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.
    DOI:  https://doi.org/10.1038/s41586-023-06956-y
  3. Histochem Cell Biol. 2024 Jan 20.
    The peroxisome: an update on mysteries 3.0.
    Rechal Kumar, Markus Islinger, Harley Worthy, Ruth Carmichael, Michael Schrader.
      Peroxisomes are highly dynamic, oxidative organelles with key metabolic functions in cellular lipid metabolism, such as the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as the regulation of cellular redox balance. Loss of peroxisomal functions causes severe metabolic disorders in humans. Furthermore, peroxisomes also fulfil protective roles in pathogen and viral defence and immunity, highlighting their wider significance in human health and disease. This has sparked increasing interest in peroxisome biology and their physiological functions. This review presents an update and a continuation of three previous review articles addressing the unsolved mysteries of this remarkable organelle. We continue to highlight recent discoveries, advancements, and trends in peroxisome research, and address novel findings on the metabolic functions of peroxisomes, their biogenesis, protein import, membrane dynamics and division, as well as on peroxisome-organelle membrane contact sites and organelle cooperation. Furthermore, recent insights into peroxisome organisation through super-resolution microscopy are discussed. Finally, we address new roles for peroxisomes in immune and defence mechanisms and in human disorders, and for peroxisomal functions in different cell/tissue types, in particular their contribution to organ-specific pathologies.
    Keywords:  Membrane contact sites; Motility; Organelle biogenesis; Organelle division; Organelle dynamics; Peroxin; Peroxisome; Protein import; STED microscopy
    DOI:  https://doi.org/10.1007/s00418-023-02259-5
  4. FEBS Lett. 2024 Jan 24.
    Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging.
    Arun T John Peter, Benoit Kornmann.
      Lipid trafficking is critical for the biogenesis and expansion of organelle membranes. Lipid transport proteins (LTPs) have been proposed to facilitate lipid transport at contact sites between organelles. Despite the fundamental importance of LTPs in cell physiology, our knowledge on the mechanisms of interorganelle lipid distribution remains poor due to the scarcity of assays to monitor lipid flux in vivo. In this review, we highlight the recent development of a versatile method named METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), which uses a combination of enzymatic mass tagging and mass spectrometry to track lipid flux between organelles inside living cells. We discuss the methodology, its distinct advantages, limitations as well as its potential to unearth the pipelines of lipid transport and LTP function in vivo.
    Keywords:  CFAse; METALIC; cyclopropane fatty acid; lipid trafficking; lipid transport assay; lipid transport protein; lipidomics; mass tagging; membrane contact sites; phospholipid
    DOI:  https://doi.org/10.1002/1873-3468.14810
  5. Int J Biol Sci. 2024 ;20(3): 831-847
    The SIRT3-ATAD3A axis regulates MAM dynamics and mitochondrial calcium homeostasis in cardiac hypertrophy.
    Zeyu Li, Ou Hu, Suowen Xu, Chenjia Lin, Wenjing Yu, Dinghu Ma, Jing Lu, Peiqing Liu.
      Mitochondria are energy-producing organelles that are mobile and harbor dynamic network structures. Although mitochondria and endoplasmic reticulum (ER) play distinct cellular roles, they are physically connected to maintain functional homeostasis. Abnormal changes in this interaction have been linked to pathological states, including cardiac hypertrophy. However, the exact regulatory molecules and mechanisms are yet to be elucidated. Here, we report that ATPase family AAA-domain containing protein 3A (ATAD3A) is an essential regulator of ER-mitochondria interplay within the mitochondria-associated membrane (MAM). ATAD3A prevents isoproterenol (ISO)-induced mitochondrial calcium accumulation, improving mitochondrial dysfunction and ER stress, which preserves cardiac function and attenuates cardiac hypertrophy. We also find that ATAD3A is a new substrate of NAD+-dependent deacetylase Sirtuin 3 (SIRT3). Notably, the heart mitochondria of SIRT3 knockout mice exhibited excessive formation of MAMs. Mechanistically, ATAD3A specifically undergoes acetylation, which reduces self-oligomerization and promotes cardiac hypertrophy. ATAD3A oligomerization is disrupted by acetylation at K134 site, and ATAD3A monomer closely interacts with the IP3R1-GRP75-VDAC1 complex, which leads to mitochondrial calcium overload and dysfunction. In summary, ATAD3A localizes to the MAMs, where it protects the homeostasis of ER-mitochondria contacts, quenching mitochondrial calcium overload and keeping mitochondrial bioenergetics unresponsive to ER stress. The SIRT3-ATAD3A axis represents a potential therapeutic target for cardiac hypertrophy.
    Keywords:  Cardiac hypertrophy; ER stress; IP3R1-GRP75-VDAC1 complex; Mitochondria; Mitochondria-associated membranes; acetylation
    DOI:  https://doi.org/10.7150/ijbs.89253
  6. J Fungi (Basel). 2024 Jan 22. pii: 87. [Epub ahead of print]10(1):
    The Endoplasmic Reticulum-Plasma Membrane Tethering Protein Ice2 Controls Lipid Droplet Size via the Regulation of Phosphatidylcholine in Candida albicans.
    Ying Deng, Hangqi Zhu, Yanting Wang, Yixuan Dong, Jiawen Du, Qilin Yu, Mingchun Li.
      Lipid droplets (LDs) are intracellular organelles that play important roles in cellular lipid metabolism; they change their sizes and numbers in response to both intracellular and extracellular signals. Changes in LD size reflect lipid synthesis and degradation and affect many cellular activities, including energy supply and membrane synthesis. Here, we focused on the function of the endoplasmic reticulum-plasma membrane tethering protein Ice2 in LD dynamics in the fungal pathogen Candida albicans (C. albicans). Nile red staining and size quantification showed that the LD size increased in the ice2Δ/Δ mutant, indicating the critical role of Ice2 in the regulation of LD dynamics. A lipid content analysis further demonstrated that the mutant had lower phosphatidylcholine levels. As revealed with GFP labeling and fluorescence microscopy, the methyltransferase Cho2, which is involved in phosphatidylcholine synthesis, had poorer localization in the plasma membrane in the mutant than in the wild-type strain. Interestingly, the addition of the phosphatidylcholine precursor choline led to the recovery of normal-sized LDs in the mutant. These results indicated that Ice2 regulates LD size by controlling intracellular phosphatidylcholine levels and that endoplasmic reticulum-plasma membrane tethering proteins play a role in lipid metabolism regulation in C. albicans. This study provides significant findings for further investigation of the lipid metabolism in fungi.
    Keywords:  Candida albicans; Ice2; endoplasmic reticulum–plasma membrane tethering protein; lipid droplet; phosphatidylcholine
    DOI:  https://doi.org/10.3390/jof10010087
  7. Basic Clin Pharmacol Toxicol. 2024 Jan 26.
    The role of ATP-binding cassette transporter G1 (ABCG1) in Alzheimer's disease: A review of the mechanisms.
    Mohsen Karbasi Yazdi, Mohaddeseh Sadat Alavi, Ali Roohbakhsh.
      The maintenance of cholesterol homeostasis is essential for central nervous system function. Consequently, factors that affect cholesterol homeostasis are linked to neurological disorders and pathologies. Among them, ATP-binding cassette transporter G1 (ABCG1) plays a significant role in atherosclerosis. However, its role in Alzheimer's disease (AD) is unclear. There is inconsistent information regarding ABCG1's role in AD. It can increase or decrease amyloid β (Aβ) levels in animals' brains. Clinical studies show that ABCG1 is involved in AD patients' impairment of cholesterol efflux capacity (CEC) in the cerebrospinal fluid (CSF). Lower Aβ levels in the CSF are correlated with ABCG1-mediated CEC dysfunction. ABCG1 modulates α-, β-, and γ-secretase activities in the plasma membrane and may affect Aβ production in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) cell compartment. Despite contradictory findings regarding ABCG1's role in AD, this review shows that ABCG1 has a role in Aβ generation via modulation of membrane secretases. It is, however, necessary to investigate the underlying mechanism(s). ABCG1 may also contribute to AD pathology through its role in apoptosis and oxidative stress. As a result, ABCG1 plays a role in AD and is a candidate for drug development.
    Keywords:  ABC transporters; ABCG1; Alzheimer's disease; Cholesterol; beta secretase
    DOI:  https://doi.org/10.1111/bcpt.13981
  8. Plant J. 2024 Jan 23.
    Mapping of cytosol-facing organelle outer membrane proximity proteome by proximity-dependent biotinylation in living Arabidopsis cells.
    Xinyue Bao, Huifang Jia, Xiaoyan Zhang, Sang Tian, Yanming Zhao, Xiangyun Li, Ping Lin, Chongyang Ma, Pengcheng Wang, Chun-Peng Song, Xiaohong Zhu.
      The cytosol-facing outer membrane (OM) of organelles communicates with other cellular compartments to exchange proteins, metabolites, and signaling molecules. Cellular surveillance systems also target OM-resident proteins to control organellar homeostasis and ensure cell survival under stress. However, the OM proximity proteomes have never been mapped in plant cells since using traditional approaches to discover OM proteins and identify their dynamically interacting partners remains challenging. In this study, we developed an OM proximity labeling (OMPL) system using biotin ligase-mediated proximity biotinylation to identify the proximity proteins of the OMs of mitochondria, chloroplasts, and peroxisomes in living Arabidopsis (Arabidopsis thaliana) cells. Using this approach, we mapped the OM proximity proteome of these three organelles under normal conditions and examined the effects of the ultraviolet-B (UV-B) or high light (HL) stress on the abundances of OM proximity proteins. We demonstrate the power of this system with the discovery of cytosolic factors and OM receptor candidates potentially involved in local protein translation and translocation. The candidate proteins that are involved in mitochondrion-peroxisome, mitochondrion-chloroplast, or peroxisome-chloroplast contacts, and in the organellar quality control system are also proposed based on OMPL analysis. OMPL-generated OM proximity proteomes are valuable sources of candidates for functional validation and suggest directions for further investigation of important questions in cell biology.
    Keywords:  Arabidopsis thaliana; Co-translational protein import; biotin protein ligase; membrane contact sites; organellar quality control; organelle outer membrane proximity labeling; organelle outer membrane proximity proteome; proximity labeling; technical advance
    DOI:  https://doi.org/10.1111/tpj.16641
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