bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022–11–06
seven papers selected by
Verena Kohler, University of Graz
  1. Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
  2. IMC10 and LMF1 mediate mitochondrial morphology by mitochondrion-pellicle contact sites in Toxoplasma gondii.
  3. ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.
  4. A snapshot of protein trafficking in SARS-CoV-2 infection.
  5. Mice Deficient in ER Protein Seipin Have Reduced Adrenal Cholesteryl Ester Lipid Droplet Formation and Utilization.
  6. Harnessing Dual-Fluorescence Lifetime Probes to Validate Regulatory Mechanisms of Organelle Interactions.
  7. Spatiotemporally mapping temperature dynamics of lysosomes and mitochondria using cascade organelle-targeting upconversion nanoparticles.
  1. Contact (Thousand Oaks). 2022 Jan-Dec;5:5
    Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
    Jonathan R Friedman.
      A fundamental role of membrane-bound organelles is the compartmentalization and organization of cellular processes. Mitochondria perform an immense number of metabolic chemical reactions and to efficiently regulate these, the organelle organizes its inner membrane into distinct morphological domains, including its characteristic cristae membranes. In recent years, a structural feature of increasing apparent importance is the inter-connection between the mitochondrial exterior and other organelles at membrane contact sites (MCSs). Mitochondria form MCSs with almost every other organelle in the cell, including the endoplasmic reticulum, lipid droplets, and lysosomes, to coordinate global cellular metabolism with mitochondrial metabolism. However, these MCSs not only facilitate the transport of metabolites between organelles, but also directly impinge on the physical shape and functional organization inside mitochondria. In this review, we highlight recent advances in our understanding of how physical connections between other organelles and mitochondria both directly and indirectly influence the internal architecture of mitochondria.
    Keywords:  Ca2+; cristae; endoplasmic reticulum; inner mitochondrial membrane; interorganelle (inter-organelle); lipid droplet; lysosome; mitochondrion (mitochondria); phospholipid
    DOI:  https://doi.org/10.1177/25152564221133267
  2. J Cell Sci. 2022 Oct 31. pii: jcs.260083. [Epub ahead of print]
    IMC10 and LMF1 mediate mitochondrial morphology by mitochondrion-pellicle contact sites in Toxoplasma gondii.
    Rodolpho Ornitz Oliveira Souza, Kylie N Jacobs, Peter S Back, Peter J Bradley, Gustavo Arrizabalaga.
      The single mitochondrion of Toxoplasma gondii is highly dynamic, being predominantly in a peripherally distributed lasso-shape in intracellular parasites and collapsed in extracellular ones. The peripheral positioning of the mitochondrion is associated with apparent contacts between the mitochondrion membrane and the parasite pellicle. The outer mitochondrial membrane-associated protein LMF1 is critical for the correct positioning of the mitochondrion. Intracellular parasites lacking LMF1 fail to form the lasso-shaped mitochondrion. To identify other proteins that tether the parasite's mitochondrion to the pellicle, we performed a yeast two-hybrid screen for LMF1 interactors. We identified 70 putative interactors localized in different cellular compartments, such as the parasite's apical end, mitochondrial membrane, and the inner membrane complex (IMC). Using protein-protein interaction assays, we confirmed the interaction of LMF1 with the pellicle protein IMC10. Conditional knockdown of IMC10 does not affect parasite viability but severely affects mitochondrial morphology in intracellular parasites and mitochondrial distribution to the daughter cells during division. In effect, IMC10 knockdown phenocopies disruption of LMF1, suggesting that these two proteins define a novel membrane tether between Toxoplasma's mitochondrion and the IMC.
    Keywords:   Toxoplasma gondii ; Inner Membrane Complex; LMF1; Membrane Contact Site; Mitochondrion
    DOI:  https://doi.org/10.1242/jcs.260083
  3. Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01448-6. [Epub ahead of print]41(5): 111583
    ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.
    Lingna Xu, Yunyi Qiu, Xufeng Wang, Weina Shang, Jian Bai, Kexin Shi, Hao Liu, Jun-Ping Liu, Liquan Wang, Chao Tong.
      Mitochondrial malfunction and autophagy defects are often concurrent phenomena associated with neurodegeneration. We show that Miga, a mitochondrial outer-membrane protein that regulates endoplasmic reticulum-mitochondrial contact sites (ERMCSs), is required for autophagy. Loss of Miga results in an accumulation of autophagy markers and substrates, whereas PI3P and Syx17 levels are reduced. Further experiments indicated that the fusion between autophagosomes and lysosomes is defective in Miga mutants. Miga binds to Atg14 and Uvrag; concordantly, Miga overexpression results in Atg14 and Uvrag recruitment to mitochondria. The heightened PI3K activity induced by Miga requires Uvrag, whereas Miga-mediated stabilization of Syx17 is dependent on Atg14. Miga-regulated ERMCSs are critical for PI3P formation but are not essential for the stabilization of Syx17. In summary, we identify a mitochondrial protein that regulates autophagy by recruiting two alternative components of the PI3K complex present at the ERMCSs.
    Keywords:  CP: Cell biology; Drosophila; ER–mitochondrial contact; autophagy; lysosome; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2022.111583
  4. Biol Cell. 2022 Oct 31.
    A snapshot of protein trafficking in SARS-CoV-2 infection.
    Vibhu Prasad, Ralf Bartenschlager.
      SARS-CoV-2 is a human pathogenic virus responsible for the COVID-19 (coronavirus disease 2019) pandemic. The infection cycle of SARS-CoV-2 involves several related steps, including virus entry, gene expression, RNA replication, assembly of infectious virions and their egress. For all of these steps, the virus relies on and exploits host cell factors, cellular organelles, and processes such as endocytosis, nuclear transport, protein secretion, metabolite transport at membrane contact sites and exocytotic pathways. To do this, SARS-CoV-2 has evolved multifunctional viral proteins that hijack cellular factors and modulate their function by unique strategies. In this Review, we highlight cellular trafficking factors, processes, and organelles of relevance to the SARS-CoV-2 infection cycle and how viral proteins make use of and perturb cellular transport during the viral infection cycle. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/boc.202200073
  5. J Lipid Res. 2022 Nov 01. pii: S0022-2275(22)00142-0. [Epub ahead of print] 100309
    Mice Deficient in ER Protein Seipin Have Reduced Adrenal Cholesteryl Ester Lipid Droplet Formation and Utilization.
    Wen-Jun Shen, Yuan Cortez, Amar Singh, Weiqin Chen, Salman Azhar, Fredric B Kraemer.
      Cholesteryl ester-rich lipid droplets accumulate in steroidogenic tissues under physiological conditions and constitute an important source of cholesterol as the precursor for the synthesis of all steroid hormones. The mechanisms specifically involved in cholesteryl ester-rich lipid droplet formation have not been directly studied and are assumed by most to occur in a fashion analogous to triacylglycerol-rich lipid droplets. Seipin is an ER protein that forms oligomeric complexes at ER-lipid droplet contact sites, and seipin deficiency results in severe alterations in lipid droplet maturation and morphology as seen in Berardinelli-Seip congenital lipodystrophy type 2. While seipin is critical for triacylglycerol-rich lipid droplet formation, no studies have directly addressed whether seipin is important for cholesteryl ester-rich lipid droplet biogenesis. To address this issue, mice with deficient expression of seipin specifically in adrenal, testis and ovary, steroidogenic tissues that accumulate cholesteryl ester-rich lipid droplets under normal physiological conditions were generated. We found that the steroidogenic-specific seipin deficient mice displayed a marked reduction in lipid droplet and cholesterol/cholesteryl ester accumulation in the adrenals, demonstrating the pivotal role of seipin in cholesteryl ester-rich lipid droplet accumulation/formation. Moreover, the reduction in cholesteryl ester-rich lipid droplets was associated with significant defects in adrenal and gonadal steroid hormone production that could not be completely reversed by addition of exogenous lipoprotein cholesterol. We conclude that seipin has a heretofore unappreciated role in intracellular cholesterol trafficking.
    Keywords:  Berardinelli-Seip congenital lipodystrophy type 2; adrenal; cholesterol; cholesterol trafficking; lipid droplet maturation; ovary; seipin deficiency; steroidogenesis; testis; triacylglycerol
    DOI:  https://doi.org/10.1016/j.jlr.2022.100309
  6. J Am Chem Soc. 2022 Nov 01.
    Harnessing Dual-Fluorescence Lifetime Probes to Validate Regulatory Mechanisms of Organelle Interactions.
    Yuping Zhao, Hyeong Seok Kim, Xiang Zou, Ling Huang, Xing Liang, Zihong Li, Jong Seung Kim, Weiying Lin.
      Organelles are dynamic yet highly organized to preserve cellular homeostasis. However, the absence of time-resolved molecular tools for simultaneous dual-signal imaging of two organelles has prevented scientists from elucidating organelle interaction regulatory mechanisms on a nanosecond timescale. To date, the regulatory mechanisms governing the interaction between endoplasmic reticulum (ER) and autophagosomes are unknown. In this study, we propose a strategy for developing dual-fluorescence lifetime probes localized to the endoplasmic reticulum and autophagosomes to investigate their interaction regulatory mechanisms. Using the robust probe CF2, we investigated the regulatory mechanisms between ER and autophagosomes and discovered the following: (i) motile autophagosome in ER tips drives the ER tubule to grow and slide; (ii) the ER reticulate tubule forms a three-way junction centered on the autophagosome; (iii) ER autophagy is a type of cell damage index during drug-induced apoptosis. Thus, this study advances our knowledge of organelle interaction regulatory mechanisms, shedding light on the identification of therapeutic targets for neurodegenerative diseases.
    DOI:  https://doi.org/10.1021/jacs.2c08966
  7. Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2207402119
    Spatiotemporally mapping temperature dynamics of lysosomes and mitochondria using cascade organelle-targeting upconversion nanoparticles.
    Xiangjun Di, Dejiang Wang, Qian Peter Su, Yongtao Liu, Jiayan Liao, Mahnaz Maddahfar, Jiajia Zhou, Dayong Jin.
      The intracellular metabolism of organelles, like lysosomes and mitochondria, is highly coordinated spatiotemporally and functionally. The activities of lysosomal enzymes significantly rely on the cytoplasmic temperature, and heat is constantly released by mitochondria as the byproduct of adenosine triphosphate (ATP) generation during active metabolism. Here, we developed temperature-sensitive LysoDots and MitoDots to monitor the in situ thermal dynamics of lysosomes and mitochondria. The design is based on upconversion nanoparticles (UCNPs) with high-density surface modifications to achieve the exceptionally high sensitivity of 2.7% K-1 and low uncertainty of 0.8 K for nanothermometry to be used in living cells. We show the measurement is independent of the ion concentrations and pH values. With Ca2+ ion shock, the temperatures of both lysosomes and mitochondria increased by ∼2 to 4 °C. Intriguingly, with chloroquine (CQ) treatment, the lysosomal temperature was observed to decrease by up to ∼3 °C, while mitochondria remained relatively stable. Lastly, with oxidative phosphorylation inhibitor treatment, we observed an ∼3 to 7 °C temperature increase and a thermal transition from mitochondria to lysosomes. These observations indicate different metabolic pathways and thermal transitions between lysosomes and mitochondria inside HeLa cells. The nanothermometry probes provide a powerful tool for multimodality functional imaging of subcellular organelles and interactions with high spatial, temporal, and thermal dynamics resolutions.
    Keywords:  lysosome; mitochondria; nanothermometry; upconversion nanoparticles (UCNPs)
    DOI:  https://doi.org/10.1073/pnas.2207402119
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