bims-mecosi Biomed News
on Membrane contact sites
Issue of 2023‒06‒11
nine papers selected by
Verena Kohler
  1. Gluing yeast peroxisomes - composition and function of membrane contact sites.
  2. PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.
  3. Editorial: the role of mitochondrial endoplasmic reticulum contact sites in human health and disease.
  4. Intracellular Cholesterol Trafficking.
  5. PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.
  6. β-carotene targets IP3R/GRP75/VDAC1-MCU axis to renovate LPS-induced mitochondrial oxidative damage by regulating STIM1.
  7. Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.
  8. Optimizing In Situ Proximity Ligation Assays for Mitochondria, ER, or MERC Markers in Skeletal Muscle Tissue and Cells.
  9. MIC26 and MIC27 are bona fide subunits of the MICOS complex in mitochondria and do not exist as glycosylated apolipoproteins.
  1. J Cell Sci. 2023 Jun 01. pii: jcs259440. [Epub ahead of print]136(11):
    Gluing yeast peroxisomes - composition and function of membrane contact sites.
    Fei Wu, Rinse de Boer, Ida J van der Klei.
      Membrane contact sites are defined as regions of close proximity between two membranes; this association is mediated by protein-protein and/or protein-lipid interactions. Contact sites are often involved in lipid transport, but also can perform other functions. Peroxisomal membrane contact sites have obtained little attention compared to those of other cell organelles. However, recent studies resulted in a big leap in our knowledge of the occurrence, composition and function of peroxisomal contact sites. Studies in yeast strongly contributed to this progress. In this Review, we present an overview of our current knowledge on peroxisomal membrane contact sites in various yeast species, including Hansenula polymorpha, Saccharomyces cerevisiae, Pichia pastoris and Yarrowia lipolytica. Yeast peroxisomes form contacts with almost all other cellular organelles and with the plasma membrane. The absence of a component of a yeast peroxisomal contact site complex results in a range of peroxisomal phenotypes, including metabolic and biogenesis defects and alterations in organelle number, size or position.
    Keywords:  Membrane contact site; Organelle; Peroxisome; Tether protein; Yeast
    DOI:  https://doi.org/10.1242/jcs.259440
  2. Dev Cell. 2023 Jun 02. pii: S1534-5807(23)00239-3. [Epub ahead of print]
    PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.
    Gregory E Miner, Christina M So, Whitney Edwards, Joey V Ragusa, Jonathan T Wine, Daniel Wong Gutierrez, Michael V Airola, Laura E Herring, Rosalind A Coleman, Eric L Klett, Sarah Cohen.
      Cells adjust their metabolism by remodeling membrane contact sites that channel metabolites to different fates. Lipid droplet (LD)-mitochondria contacts change in response to fasting, cold exposure, and exercise. However, their function and mechanism of formation have remained controversial. We focused on perilipin 5 (PLIN5), an LD protein that tethers mitochondria, to probe the function and regulation of LD-mitochondria contacts. We demonstrate that efficient LD-to-mitochondria fatty acid (FA) trafficking and ß-oxidation during starvation of myoblasts are promoted by phosphorylation of PLIN5 and require an intact PLIN5 mitochondrial tethering domain. Using human and murine cells, we further identified the acyl-CoA synthetase, FATP4 (ACSVL4), as a mitochondrial interactor of PLIN5. The C-terminal domains of PLIN5 and FATP4 constitute a minimal protein interaction capable of inducing organelle contacts. Our work suggests that starvation leads to phosphorylation of PLIN5, lipolysis, and subsequent channeling of FAs from LDs to FATP4 on mitochondria for conversion to fatty-acyl-CoAs and subsequent oxidation.
    Keywords:  FATP4; PLIN5; acyl-CoA; fatty acids; lipid droplets; membrane contact sites; metabolism; mitochondria; organelles
    DOI:  https://doi.org/10.1016/j.devcel.2023.05.006
  3. Front Mol Biosci. 2023 ;10 1223354
    Editorial: the role of mitochondrial endoplasmic reticulum contact sites in human health and disease.
    Prasanna Katti, Sharifa Love-Rutledge, Sandra A Murray, Antentor Hinton.
      
    Keywords:  MERCs; contact sites; disease; mitochondria; pathology
    DOI:  https://doi.org/10.3389/fmolb.2023.1223354
  4. Cold Spring Harb Perspect Biol. 2023 Jun 05. pii: a041404. [Epub ahead of print]
    Intracellular Cholesterol Trafficking.
    Elina Ikonen, Vesa M Olkkonen.
      Cholesterol is an essential lipid species of mammalian cells. Cells acquire it through synthesis in the endoplasmic reticulum (ER) and uptake from lipoprotein particles. Newly synthesized cholesterol is efficiently distributed from the ER to other organelles via lipid-binding/transfer proteins concentrated at membrane contact sites (MCSs) to reach the trans-Golgi network, endosomes, and plasma membrane. Lipoprotein-derived cholesterol is exported from the plasma membrane and endosomal compartments via a combination of vesicle/tubule-mediated membrane transport and transfer through MCSs. In this review, we provide an overview of intracellular cholesterol trafficking pathways, including cholesterol flux from the ER to other membranes, cholesterol uptake from lipoprotein donors and transport from the plasma membrane to the ER, cellular cholesterol efflux to lipoprotein acceptors, as well as lipoprotein cholesterol secretion from enterocytes, hepatocytes, and astrocytes. We also briefly discuss human diseases caused by defects in these processes and therapeutic strategies available in such conditions.
    DOI:  https://doi.org/10.1101/cshperspect.a041404
  5. Autophagy. 2023 Jun 08.
    PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.
    Hao Liu, Wenxia Shao, Wei Liu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation-the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.
    Keywords:  Drosophila; Golgi apparatus; PtdIns4P; endoplasmic reticulum-autolysosome contacts
    DOI:  https://doi.org/10.1080/15548627.2023.2222556
  6. Free Radic Biol Med. 2023 Jun 02. pii: S0891-5849(23)00437-9. [Epub ahead of print]205 25-46
    β-carotene targets IP3R/GRP75/VDAC1-MCU axis to renovate LPS-induced mitochondrial oxidative damage by regulating STIM1.
    Meijuan Meng, Yijin Jiang, Yan Wang, Ran Huo, Nana Ma, Xiangzhen Shen, Guangjun Chang.
      Endoplasmic reticulum (ER) and mitochondria are the main sites for the storage and regulation of Ca2+ homeostasis. An imbalance of Ca2+ homeostasis can cause ER stress and mitochondrial dysfunction, thereby inducing apoptosis. The store-operated calcium entry (SOCE) is the main channel for extracellular calcium influx. Mitochondria-associated endoplasmic reticulum (MAM) is an important agent for Ca2+ transfer from the ER to the mitochondria. Therefore, regulation of SOCE and MAMs has potential therapeutic value for disease prevention and treatment. In this study, bovine mammary epithelial cells (BMECs) and mice were used as models to explore the mechanisms of β-carotene to relieve ER stress and mitochondrial dysfunction. BAPTA-AM, EGTA (Ca2+ inhibitor), and BTP2 (SOCE channel inhibitor) alleviated ER stress and mitochondrial oxidative damage induced by increased intracellular Ca2+ levels after lipopolysaccharide (LPS) stimulation. Furthermore, inhibition of ER stress by 4-PBA (ER stress inhibitor), 2-APB (IP3R inhibitor), and ruthenium red (mitochondrial calcium uniporter (MCU) inhibitor) restored mitochondrial function by reducing mitochondrial ROS. Our data also confirm that β-carotene targeted STIM1 and IP3R channels to repair LPS-induced ER stress and mitochondrial disorders. Consistent with the in vitro study, in vito experiments in mice further showed that β-carotene attenuated LPS-induced ER stress and mitochondrial oxidative damage by inhibiting the expression of STIM1 and ORAI1, and reducing the level of Ca2+ in mouse mammary glands. Therefore, ER stress-mitochondrial oxidative damage mediated by the STIM1-ER-IP3R/GRP75/VDAC1-MCU axis plays an vital role in the development of mastitis. Our results provided novel ideas and therapeutic targets for the prevention and treatment of mastitis.
    Keywords:  ER stress; IP3R-GRP75-VDAC1 channel; MAMs; Mitochondria; SOCE; β-carotene
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.021
  7. Neurochem Res. 2023 Jun 09.
    Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.
    Mengjie Chen, Ruyu Yan, Lingling Ding, Jiansheng Luo, Jiaqi Ning, Ruiling Zhou.
      Perioperative neurocognitive disorders (PND) increases postoperative dementia and mortality in patients and has no effective treatment. Although the detailed pathogenesis of PND is still elusive, a large amount of evidence suggests that damaged mitochondria may play an important role in the pathogenesis of PND. A healthy mitochondrial pool not only provides energy for neuronal metabolism but also maintains neuronal activity through other mitochondrial functions. Therefore, exploring the abnormal mitochondrial function in PND is beneficial for finding promising therapeutic targets for this disease. This article summarizes the research advances of mitochondrial energy metabolism disorder, inflammatory response and oxidative stress, mitochondrial quality control, mitochondria-associated endoplasmic reticulum membranes, and cell death in the pathogenesis of PND, and briefly describes the application of mitochondria-targeted therapies in PND.
    Keywords:  Anesthesia/surgery; Inflammation; Mitochondrial dynamics; Mitochondrial dysfunction; Oxidative stress; Perioperative neurocognitive disorders
    DOI:  https://doi.org/10.1007/s11064-023-03962-4
  8. bioRxiv. 2023 May 22. pii: 2023.05.20.541599. [Epub ahead of print]
    Optimizing In Situ Proximity Ligation Assays for Mitochondria, ER, or MERC Markers in Skeletal Muscle Tissue and Cells.
    Dominique C Stephens, Amber Crabtree, Heather K Beasley, Edgar Garza-Lopez, Kit Neikirk, Margaret Mungai, Larry Vang, Zer Vue, Neng Vue, Andrea G Marshall, Kyrin Turner, Jianqiang Shao, Sandra Murray, Jennifer A Gaddy, Celestine Wanjalla, Jamaine Davis, Steven Damo, Antentor O Hinton.
      Proximity ligation assays (PLA) use specific antibodies to detect endogenous protein-protein interactions. PLA is a highly useful biochemical technique that allows two proteins within close proximity to be visualized with fluorescent probes amplified by PCR. While this technique has gained prominence, the use of PLA in mouse skeletal muscle (SkM) is novel. In this article, we discuss how the PLA method can be used in SkM to study the protein-protein interactions within mitochondria-endoplasmic reticulum contact sites (MERCs).Tweetable Abstract: Proximity Ligation Assays can be used in skeletal muscle tissue and myoblasts to explore the protein-protein interactions involved in MERC sites.
    Highlights: Skeletal muscle tissue and cells are plated on glass coverslips for evaluation by proximity ligation assay (PLA).Following fixation, cells are probed and stained for Mfn1, Mfn2, mitochondria, and ER and imaged using fluorescence confocal microscopy.This method shows that PLA can be used in mouse SkM and is adaptable to other models.Protocol for detection of protein-protein interactions using PLA.
    Key Resources Table:
    DOI:  https://doi.org/10.1101/2023.05.20.541599
  9. PLoS One. 2023 ;18(6): e0286756
    MIC26 and MIC27 are bona fide subunits of the MICOS complex in mitochondria and do not exist as glycosylated apolipoproteins.
    Melissa Lubeck, Nick H Derkum, Ritam Naha, Rebecca Strohm, Marc D Driessen, Bengt-Frederik Belgardt, Michael Roden, Kai Stühler, Ruchika Anand, Andreas S Reichert, Arun Kumar Kondadi.
      Impairments of mitochondrial functions are linked to human ageing and pathologies such as cancer, cardiomyopathy, neurodegeneration and diabetes. Specifically, aberrations in ultrastructure of mitochondrial inner membrane (IM) and factors regulating them are linked to diabetes. The development of diabetes is connected to the 'Mitochondrial Contact Site and Cristae Organising System' (MICOS) complex which is a large membrane protein complex defining the IM architecture. MIC26 and MIC27 are homologous apolipoproteins of the MICOS complex. MIC26 has been reported as a 22 kDa mitochondrial and a 55 kDa glycosylated and secreted protein. The molecular and functional relationship between these MIC26 isoforms has not been investigated. In order to understand their molecular roles, we depleted MIC26 using siRNA and further generated MIC26 and MIC27 knockouts (KOs) in four different human cell lines. In these KOs, we used four anti-MIC26 antibodies and consistently detected the loss of mitochondrial MIC26 (22 kDa) and MIC27 (30 kDa) but not the loss of intracellular or secreted 55 kDa protein. Thus, the protein assigned earlier as 55 kDa MIC26 is nonspecific. We further excluded the presence of a glycosylated, high-molecular weight MIC27 protein. Next, we probed GFP- and myc-tagged variants of MIC26 with antibodies against GFP and myc respectively. Again, only the mitochondrial versions of these tagged proteins were detected but not the corresponding high-molecular weight MIC26, suggesting that MIC26 is indeed not post-translationally modified. Mutagenesis of predicted glycosylation sites in MIC26 also did not affect the detection of the 55 kDa protein band. Mass spectrometry of a band excised from an SDS gel around 55 kDa could not confirm the presence of any peptides derived from MIC26. Taken together, we conclude that both MIC26 and MIC27 are exclusively localized in mitochondria and that the observed phenotypes reported previously are exclusively due to their mitochondrial function.
    DOI:  https://doi.org/10.1371/journal.pone.0286756
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