bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024–05–26
ten papers selected by
Verena Kohler, Umeå University
  1. Emerging functions of the mitochondria-ER-lipid droplet three-way junction in coordinating lipid transfer, metabolism, and storage in cells.
  2. KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
  3. The molecular mechanism of on-demand sterol biosynthesis at organelle contact sites.
  4. Mitochondria-ER-PM contacts regulate mitochondrial division and PI(4)P distribution.
  5. Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia.
  6. Ethnicity-related differences in mitochondrial regulation by insulin stimulation in diabetes.
  7. Newsights of endoplasmic reticulum in hypoxia.
  8. Lipidomics reveals the reshaping of the mitochondrial phospholipid profile in cells lacking OPA1 and Mitofusins.
  9. Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes.
  10. Building a biofactory: Constructing glandular trichomes in Cannabis sativa.
  1. FEBS Lett. 2024 May;598(10): 1252-1273
    Emerging functions of the mitochondria-ER-lipid droplet three-way junction in coordinating lipid transfer, metabolism, and storage in cells.
    Vera Filipa Monteiro-Cardoso, Francesca Giordano.
      Over the past two decades, we have witnessed a growing appreciation for the importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where the membranes of two organelles meet but do not fuse and allow the transfer of metabolites between organelles, playing crucial roles in the coordination of cellular metabolic activities. The significant advancements in imaging techniques and molecular and cell biology research have revealed that CS are more complex than what originally thought, and as they are extremely dynamic, they can remodel their shape, composition, and functions in accordance with metabolic and environmental changes and can occur between more than two organelles. Here, we describe how recent studies led to the identification of a three-way mitochondria-ER-lipid droplet CS and discuss the emerging functions of these contacts in maintaining lipid storage, homeostasis, and balance. We also summarize the properties and functions of key protein components localized at the mitochondria-ER-lipid droplet interface, with a special focus on lipid transfer proteins. Understanding tripartite CS is essential for unraveling the complexities of inter-organelle communication and cooperation within cells.
    Keywords:  MAM; contact sites; fatty acids; lipid metabolism; lipid transfer proteins
    DOI:  https://doi.org/10.1002/1873-3468.14893
  2. J Cell Sci. 2024 May 24. pii: jcs.261728. [Epub ahead of print]
    KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
    Peace Atakpa-Adaji, Adelina Ivanova, Karolina Kujawa, Colin W Taylor.
      Inositol 1,4,5-trisphosphate receptors (IP3Rs) are high-conductance channels that allow the regulated redistribution of Ca2+ from the ER to the cytosol and, at specialised membrane contact sites (MCS), to other organelles. Only a subset of IP3Rs release Ca2+ to the cytosol in response to IP3. These 'licensed' IP3Rs are associated with Kras-induced actin-interacting protein (KRAP) beneath the plasma membrane. It is unclear whether KRAP regulates IP3Rs at MCS. We show, using simultaneous measurements of Ca2+ concentration in the cytosol and mitochondrial matrix, that KRAP also licenses IP3Rs to release Ca2+ to mitochondria. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors. KRAP is located at ER-mitochondria membrane contact sites (ERMCS) populated by IP3R clusters. Using a proximity ligation assay between IP3R and voltage-dependent anion channel 1 (VDAC1), we show that loss of KRAP reduces the number of ERMCS. We conclude that KRAP regulates Ca2+ transfer from IP3Rs to mitochondria by both licensing IP3R activity and stabilizing ERMCS.
    Keywords:  Ca2+; Endoplasmic reticulum; HeLa cell; Histamine; IP3 receptor; KRAP; MCU; Membrane contact site; Mitochondria; Proximity ligation assay; VDAC1
    DOI:  https://doi.org/10.1242/jcs.261728
  3. bioRxiv. 2024 May 12. pii: 2024.05.09.593285. [Epub ahead of print]
    The molecular mechanism of on-demand sterol biosynthesis at organelle contact sites.
    Naama Zung, Nitya Aravindan, Angela Boshnakovska, Rosario Valenti, Noga Preminger, Felix Jonas, Gilad Yaakov, Mathilda M Willoughby, Bettina Homberg, Jenny Keller, Meital Kupervaser, Nili Dezorella, Tali Dadosh, Sharon G Wolf, Maxim Itkin, Sergey Malitsky, Alexander Brandis, Naama Barkai, Rubén Fernández-Busnadiego, Amit R Reddi, Peter Rehling, Doron Rapaport, Maya Schuldiner.
      Contact-sites are specialized zones of proximity between two organelles, essential for organelle communication and coordination. The formation of contacts between the Endoplasmic Reticulum (ER), and other organelles, relies on a unique membrane environment enriched in sterols. However, how these sterol-rich domains are formed and maintained had not been understood. We found that the yeast membrane protein Yet3, the homolog of human BAP31, is localized to multiple ER contact sites. We show that Yet3 interacts with all the enzymes of the post-squalene ergosterol biosynthesis pathway and recruits them to create sterol-rich domains. Increasing sterol levels at ER contacts causes its depletion from the plasma membrane leading to a compensatory reaction and altered cell metabolism. Our data shows that Yet3 provides on-demand sterols at contacts thus shaping organellar structure and function. A molecular understanding of this protein's functions gives new insights into the role of BAP31 in development and pathology.
    DOI:  https://doi.org/10.1101/2024.05.09.593285
  4. J Cell Biol. 2024 Sep 02. pii: e202308144. [Epub ahead of print]223(9):
    Mitochondria-ER-PM contacts regulate mitochondrial division and PI(4)P distribution.
    Jason C Casler, Clare S Harper, Antoineen J White, Heidi L Anderson, Laura L Lackner.
      The mitochondria-ER-cortex anchor (MECA) forms a tripartite membrane contact site between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM). The core component of MECA, Num1, interacts with the PM and mitochondria via two distinct lipid-binding domains; however, the molecular mechanism by which Num1 interacts with the ER is unclear. Here, we demonstrate that Num1 contains a FFAT motif in its C-terminus that interacts with the integral ER membrane protein Scs2. While dispensable for Num1's functions in mitochondrial tethering and dynein anchoring, the FFAT motif is required for Num1's role in promoting mitochondrial division. Unexpectedly, we also reveal a novel function of MECA in regulating the distribution of phosphatidylinositol-4-phosphate (PI(4)P). Breaking Num1 association with any of the three membranes it tethers results in an accumulation of PI(4)P on the PM, likely via disrupting Sac1-mediated PI(4)P turnover. This work establishes MECA as an important regulatory hub that spatially organizes mitochondria, ER, and PM to coordinate crucial cellular functions.
    DOI:  https://doi.org/10.1083/jcb.202308144
  5. Acta Biochim Biophys Sin (Shanghai). 2024 May 22.
    Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia.
    Andi Wang, Zhuo Li, Dan Zhang, Chang Chen, Hua Zhang.
      Autophagy dysregulation and Ca 2+-induced mitochondrial dysfunction in trophoblast cells are proposed to contribute to preeclampsia (PE) development. FAM134B is identified as a receptor associated with endoplasmic reticulum autophagy (ER-phagy). In this study, the placentas of normal pregnant women and PE patients are collected and analyzed by immunohistochemistry, quantitative real-time PCR, and western blot analysis. The effects of ER-phagy are investigated in HTR8/SVneo cells. Significantly increased levels of FAM134B, inositol-1,4,5-triphosphate receptor type 1 (IP3R), calnexin, cleaved caspase 3 and cytochrome C are detected in the PE placenta and sodium nitroprusside (SNP)-treated HTR-8/SVneo cells. Overexpression of FAM134B in HTR-8/SVneo cells results in increased apoptosis, impaired invasion capacity, and diminished mitochondrial function, while an autophagy inhibitor improves mitochondrial performance. Excessive ER-phagy is also associated with an increased concentration of gamma linolenic acid. Our findings suggest that FAM134B contributes to trophoblast apoptosis by mediating ER-mitochondria Ca 2+ transfer through mitochondria-associated endoplasmic reticulum membranes (MAMs) and subsequent mitochondrial function, further enhancing our understanding of PE etiology.
    Keywords:  endoplasmic reticulum autophagy (ER-phagy); lipidomic metabolome; mitochondria-associated endoplasmic reticulum membrane; mitochondrial dysfunction; preeclampsia
    DOI:  https://doi.org/10.3724/abbs.2024065
  6. J Cell Physiol. 2024 May 22.
    Ethnicity-related differences in mitochondrial regulation by insulin stimulation in diabetes.
    Kit Neikirk, Kinuthia Kabugi, Margaret Mungai, Bartosz Kula, Nathan Smith, Antentor O Hinton.
      Mitochondrial dysfunction has long been implicated in the development of insulin resistance, which is a hallmark of type 2 diabetes. However, recent studies reveal ethnicity-related differences in mitochondrial processes, underscoring the need for nuance in studying mitochondrial dysfunction and insulin sensitivity. Furthermore, the higher prevalence of type 2 diabetes among African Americans and individuals of African descent has brought attention to the role of ethnicity in disease susceptibility. In this review, which covers existing literature, genetic studies, and clinical data, we aim to elucidate the complex relationship between mitochondrial alterations and insulin stimulation by considering how mitochondrial dynamics, contact sites, pathways, and metabolomics may be differentially regulated across ethnicities, through mechanisms such as single nucleotide polymorphisms (SNPs). In addition to achieving a better understanding of insulin stimulation, future studies identifying novel regulators of mitochondrial structure and function could provide valuable insights into ethnicity-dependent insulin signaling and personalized care.
    Keywords:  diabetes; health disparities; individualized care; insulin; mitochondria
    DOI:  https://doi.org/10.1002/jcp.31317
  7. Biomed Pharmacother. 2024 May 22. pii: S0753-3322(24)00696-6. [Epub ahead of print]175 116812
    Newsights of endoplasmic reticulum in hypoxia.
    Lu Guan, Rili Ge, Shuang Ma.
      The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular homeostasis is disrupted, ER quality control (ERQC) system is activated effectively to remove misfolded and unfolded proteins through ER-phagy, ER-related degradation (ERAD), and molecular chaperones. When unfolded protein response (UPR) and ER stress are activated, the cell may be suffering a huge blow, and the most probable consequence is apoptosis. The membrane contact points between the ER and sub-organelles contribute to communication between the organelles. The decrease in oxygen concentration affects the morphology and structure of the ER, thereby affecting its function and further disrupting the stable state of cells, leading to the occurrence of disease. In this study, we describe the functions of ER-, ERQC-, and ER-related membrane contact points and their changes under hypoxia, which will help us further understand ER and treat ER-related diseases.
    Keywords:  ER stress; Endoplasmic reticulum; Hypoxia; MERCs; Mitochondrial; UPR
    DOI:  https://doi.org/10.1016/j.biopha.2024.116812
  8. J Lipid Res. 2024 May 17. pii: S0022-2275(24)00068-3. [Epub ahead of print] 100563
    Lipidomics reveals the reshaping of the mitochondrial phospholipid profile in cells lacking OPA1 and Mitofusins.
    Andrea Castellaneta, Ilario Losito, Vito Porcelli, Serena Barile, Alessandra Maresca, Valentina Del Dotto, Valentina Losacco, Ludovica Sofia Guadalupi, Cosima Damiana Calvano, David C Chan, Valerio Carelli, Luigi Palmieri, Tommaso R I Cataldi.
      Depletion or mutations of key proteins for mitochondrial fusion, like optic atrophy 1 (OPA1) and Mitofusins 1 and 2 (Mfn 1 and 2), are known to significantly impact the mitochondrial ultrastructure, suggesting alterations of their membranes' lipid profiles. In order to make an insight into this issue, we used hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray ionization-high resolution mass spectrometry to investigate the mitochondrial phospholipid (PL) profile of mouse embryonic fibroblasts (MEFs) knocked out for OPA1 and Mfn1/2 genes. 167 different sum compositions were recognized for the four major PL classes of mitochondria, namely phosphatidylcholines (PC, 63), phosphatidylethanolamines (PE, 55), phosphatidylinositols (PI, 21) and cardiolipins (CL, 28). A slight decrease in the CL/PC ratio was found for Mfn1/2-knock out mitochondria. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were subsequently used to further process HILIC-ESI-MS data. A progressive decrease in the incidence of alk(en)yl/acyl species in PC and PE classes and a general increase in the incidence of unsaturated acyl chains across all the investigated PL classes was inferred in OPA1 and Mfn1/2 knockouts compared to wild-type MEFs. These findings suggest a reshaping of the PL profile consistent with the changes observed in the mitochondrial ultrastructure when fusion proteins are absent. Based on the existing knowledge on the metabolism of mitochondrial phospholipids, we propose that fusion proteins, especially mitofusins, might influence the PL transfer between the mitochondria and the endoplasmic reticulum, likely in the context of mitochondria-associated membranes (MAMs).
    Keywords:  OPA1; glycerophospholipids; high resolution mass spectrometry; hydrophilic interaction liquid chromatography; lipidomics; mitochondria; mitofusins; mouse embryonic fibroblasts; phospholipids; phospholipids/biosynthesis
    DOI:  https://doi.org/10.1016/j.jlr.2024.100563
  9. J Cell Physiol. 2024 May 21.
    Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes.
    Bryanna Shao, Mason Killion, Ashton Oliver, Chia Vang, Faben Zeleke, Kit Neikirk, Zer Vue, Edgar Garza-Lopez, Jian-Qiang Shao, Margaret Mungai, Jacob Lam, Qiana Williams, Christopher T Altamura, Aaron Whiteside, Kinuthia Kabugi, Jessica McKenzie, Maria Ezedimma, Han Le, Alice Koh, Estevão Scudese, Larry Vang, Andrea G Marshall, Amber Crabtree, Janelle I Tanghal, Dominique Stephens, Ho-Jin Koh, Brenita C Jenkins, Sandra A Murray, Anthonya T Cooper, Clintoria Williams, Steven M Damo, Melanie R McReynolds, Jennifer A Gaddy, Celestine N Wanjalla, Heather K Beasley, Antentor Hinton.
      The sorting and assembly machinery (SAM) Complex is responsible for assembling β-barrel proteins in the mitochondrial membrane. Comprising three subunits, Sam35, Sam37, and Sam50, the SAM complex connects the inner and outer mitochondrial membranes by interacting with the mitochondrial contact site and cristae organizing system complex. Sam50, in particular, stabilizes the mitochondrial intermembrane space bridging (MIB) complex, which is crucial for protein transport, respiratory chain complex assembly, and regulation of cristae integrity. While the role of Sam50 in mitochondrial structure and metabolism in skeletal muscle remains unclear, this study aims to investigate its impact. Serial block-face-scanning electron microscopy and computer-assisted 3D renderings were employed to compare mitochondrial structure and networking in Sam50-deficient myotubes from mice and humans with wild-type (WT) myotubes. Furthermore, autophagosome 3D structure was assessed in human myotubes. Mitochondrial metabolic phenotypes were assessed using Gas Chromatography-Mass Spectrometry-based metabolomics to explore differential changes in WT and Sam50-deficient myotubes. The results revealed increased mitochondrial fragmentation and autophagosome formation in Sam50-deficient myotubes compared to controls. Metabolomic analysis indicated elevated metabolism of propanoate and several amino acids, including ß-Alanine, phenylalanine, and tyrosine, along with increased amino acid and fatty acid metabolism in Sam50-deficient myotubes. Furthermore, impairment of oxidative capacity was observed upon Sam50 ablation in both murine and human myotubes, as measured with the XF24 Seahorse Analyzer. Collectively, these findings support the critical role of Sam50 in establishing and maintaining mitochondrial integrity, cristae structure, and mitochondrial metabolism. By elucidating the impact of Sam50-deficiency, this study enhances our understanding of mitochondrial function in skeletal muscle.
    Keywords:  3D reconstruction; MICOS; SAM complex; Sam50; mitochondria
    DOI:  https://doi.org/10.1002/jcp.31293
  10. Curr Opin Plant Biol. 2024 May 17. pii: S1369-5266(24)00040-2. [Epub ahead of print]80 102549
    Building a biofactory: Constructing glandular trichomes in Cannabis sativa.
    Jessica Hancock, Samuel J Livingston, Lacey Samuels.
      Flowers of Cannabis sativa L. are densely covered with glandular trichomes containing cannabis resin that is used for medicinal and recreational purposes. The highly productive glandular trichomes have been described as 'biofactories.' In this review, we use this analogy to highlight recent advances in cannabis cell biology, metabolomics, and transcriptomics. The biofactory is built by epidermal outgrowths that differentiate into peltate-like glandular trichome heads, consisting of a disc of interconnected secretory cells with unique cellular structures. Cannabinoid and terpenoid products are warehoused in the extracellular storage cavity. Finally, multicellular stalks raise the glandular heads above the epidermis, giving cannabis flower their frosty appearance.
    Keywords:  Cannabinoid synthases; Cannabis sativa L.; Cell wall; Cuticle; Glandular trichomes; Membrane contact sites; Non-photosynthetic plastids
    DOI:  https://doi.org/10.1016/j.pbi.2024.102549
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