bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022–09–04
eight papers selected by
Verena Kohler, Stockholm University
  1. Mitochondria-Associated Endoplasmic Reticulum Membranes: Inextricably Linked with Autophagy Process.
  2. Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis.
  3. The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2.
  4. Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B+ vesicle pathway in liver cancer.
  5. Identification of two pathways mediating protein targeting from ER to lipid droplets.
  6. Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
  7. Structural insights into crista junction formation by the Mic60-Mic19 complex.
  8. Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
  1. Oxid Med Cell Longev. 2022 ;2022 7086807
    Mitochondria-Associated Endoplasmic Reticulum Membranes: Inextricably Linked with Autophagy Process.
    Chonghao Ji, Zhanwei Zhang, Zechuan Li, Xiao She, Xiaoya Wang, Binyang Li, Xin Xu, Dawei Song, Dongjiao Zhang.
      Mitochondria-associated membranes (MAMs), physical connection sites between the endoplasmic reticulum (ER) and the outer mitochondrial membrane (OMM), are involved in numerous cellular processes, such as calcium ion transport, lipid metabolism, autophagy, ER stress, mitochondria morphology, and apoptosis. Autophagy is a highly conserved intracellular process in which cellular contents are delivered by double-membrane vesicles, called autophagosomes, to the lysosomes for destruction and recycling. Autophagy, typically triggered by stress, eliminates damaged or redundant protein molecules and organelles to maintain regular cellular activity. Dysfunction of MAMs or autophagy is intimately associated with various diseases, including aging, cardiovascular, infections, cancer, multiple toxic agents, and some genetic disorders. Increasing evidence has shown that MAMs play a significant role in autophagy development and maturation. In our study, we concentrated on two opposing functions of MAMs in autophagy: facilitating the formation of autophagosomes and inhibiting autophagy. We recognized the link between MAMs and autophagy in the occurrence and progression of the diseases and therefore collated and summarized the existing intrinsic molecular mechanisms. Furthermore, we draw attention to several crucial data and open issues in the area that may be helpful for further study.
    DOI:  https://doi.org/10.1155/2022/7086807
  2. Front Cell Dev Biol. 2022 ;10 950767
    Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis.
    Naomi Hartopp, Dawn H W Lau, Sandra M Martin-Guerrero, Andrea Markovinovic, Gábor M Mórotz, Jenny Greig, Elizabeth B Glennon, Claire Troakes, Patricia Gomez-Suaga, Wendy Noble, Christopher C J Miller.
      Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many neuronal functions that are perturbed in amyotrophic lateral sclerosis (ALS) and perturbation to ER-mitochondria signaling is seen in cell and transgenic models of ALS. However, there is currently little evidence that ER-mitochondria signaling is altered in human ALS. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitochondrial surface. The VAPB-PTPI51 tethers are now known to regulate a number of ER-mitochondria signaling functions. These include delivery of Ca2+ from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and ALS spinal cords. We show that VAPB protein levels are reduced in ALS. Proximity ligation assays were then used to quantify the VAPB-PTPIP51 interaction in spinal cord motor neurons in control and ALS cases. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in ALS. Thus, we identify a new pathogenic event in post-mortem ALS.
    Keywords:  PTPIP51; VAPB; amyotrophic lateral sclerosis; endoplasmic reticulum; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2022.950767
  3. Mol Biol Cell. 2022 Aug 31. mbcE22040139
    The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2.
    Luis Bonet-Ponce, Mark R Cookson.
      Lysosomes are dynamic organelles that can remodel their membrane as an adaptive response to various cell signaling events including membrane damage. Recently, we have discovered that damaged lysosomes form and sort tubules into moving vesicles. We named this process LYTL for LYsosomal Tubulation/ sorting driven by LRRK2, as the Parkinson's disease protein LRRK2 promotes tubulation by recruiting the motor adaptor protein JIP4 to lysosomes via phosphorylated RAB proteins. Here we use spinning-disk microscopy combined with super-resolution to further characterize LYTL after membrane damage with LLOMe. We identified the endoplasmic reticulum (ER) colocalizing with sites of fission of lysosome-derived tubules. In addition, modifying the morphology of the ER by reducing ER tubules leads to a decrease in LYTL sorting suggesting that contact with tubular ER is necessary for lysosomal membrane sorting. Given the central roles of LRRK2 and lysosomal biology in PD, these discoveries are likely relevant to disease pathology and highlight interactions between organelles in this model. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E22-04-0139
  4. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2202730119
    Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B+ vesicle pathway in liver cancer.
    Kohji Yamada, Saya Motohashi, Tsunekazu Oikawa, Naoko Tago, Rei Koizumi, Masaya Ono, Toshiaki Tachibana, Ayano Yoshida, Saishu Yoshida, Masayuki Shimoda, Masahiro Oka, Yoshihiro Yoneda, Kiyotsugu Yoshida.
      Protein secretion in cancer cells defines tumor survival and progression by orchestrating the microenvironment. Studies suggest the occurrence of active secretion of cytosolic proteins in liver cancer and their involvement in tumorigenesis. Here, we investigated the identification of extended-synaptotagmin 1 (E-Syt1), an endoplasmic reticulum (ER)-bound protein, as a key mediator for cytosolic protein secretion at the ER-plasma membrane (PM) contact sites. Cytosolic proteins interacted with E-Syt1 on the ER, and then localized spatially inside SEC22B+ vesicles of liver cancer cells. Consequently, SEC22B on the vesicle tethered to the PM via Q-SNAREs (SNAP23, SNX3, and SNX4) for their secretion. Furthermore, inhibiting the interaction of protein kinase Cδ (PKCδ), a liver cancer-specific secretory cytosolic protein, with E-Syt1 by a PKCδ antibody, decreased in both PKCδ secretion and tumorigenicity. Results reveal the role of ER-PM contact sites in cytosolic protein secretion and provide a basis for ER-targeting therapy for liver cancer.
    Keywords:  PKCδ; SEC22B; cytosolic protein secretion; endoplasmic reticulum (ER); liver cancer
    DOI:  https://doi.org/10.1073/pnas.2202730119
  5. Nat Cell Biol. 2022 Sep 01.
    Identification of two pathways mediating protein targeting from ER to lipid droplets.
    Jiunn Song, Arda Mizrak, Chia-Wei Lee, Marcelo Cicconet, Zon Weng Lai, Wei-Chun Tang, Chieh-Han Lu, Stephanie E Mohr, Robert V Farese, Tobias C Walther.
      Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD-ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.
    DOI:  https://doi.org/10.1038/s41556-022-00974-0
  6. J Cell Biol. 2022 Oct 03. pii: e202206140. [Epub ahead of print]221(10):
    Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
    Yvette C Wong, Soojin Kim, Jasmine Cisneros, Catherine G Molakal, Pingping Song, Steven J Lubbe, Dimitri Krainc.
      Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson's disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy-linked mutant Mid51, which does not inhibit Mid51/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria-lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.
    DOI:  https://doi.org/10.1083/jcb.202206140
  7. Sci Adv. 2022 Sep 02. 8(35): eabo4946
    Structural insights into crista junction formation by the Mic60-Mic19 complex.
    Tobias Bock-Bierbaum, Kathrin Funck, Florian Wollweber, Elisa Lisicki, Karina von der Malsburg, Alexander von der Malsburg, Janina Laborenz, Jeffrey K Noel, Manuel Hessenberger, Sibylle Jungbluth, Carola Bernert, Séverine Kunz, Dietmar Riedel, Hauke Lilie, Stefan Jakobs, Martin van der Laan, Oliver Daumke.
      Mitochondrial cristae membranes are the oxidative phosphorylation sites in cells. Crista junctions (CJs) form the highly curved neck regions of cristae and are thought to function as selective entry gates into the cristae space. Little is known about how CJs are generated and maintained. We show that the central coiled-coil (CC) domain of the mitochondrial contact site and cristae organizing system subunit Mic60 forms an elongated, bow tie-shaped tetrameric assembly. Mic19 promotes Mic60 tetramerization via a conserved interface between the Mic60 mitofilin and Mic19 CHCH (CC-helix-CC-helix) domains. Dimerization of mitofilin domains exposes a crescent-shaped membrane-binding site with convex curvature tailored to interact with the curved CJ neck. Our study suggests that the Mic60-Mic19 subcomplex traverses CJs as a molecular strut, thereby controlling CJ architecture and function.
    DOI:  https://doi.org/10.1126/sciadv.abo4946
  8. Mol Cell. 2022 Aug 25. pii: S1097-2765(22)00758-4. [Epub ahead of print]
    Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
    Andrew Murley, Kevin Wickham, Andrew Dillin.
      Cellular quiescence-reversible exit from the cell cycle-is an important feature of many cell types important for organismal health. Quiescent cells activate protective mechanisms that allow their persistence in the absence of growth and division for long periods of time. Aging and cellular dysfunction compromise the survival and re-activation of quiescent cells over time. Counteracting this decline are two interconnected organelles that lie at opposite ends of the secretory pathway: the endoplasmic reticulum and lysosomes. In this review, we highlight recent studies exploring the roles of these two organelles in quiescent cells from diverse contexts and speculate on potential other roles they may play, such as through organelle contact sites. Finally, we discuss emerging models of cellular quiescence, utilizing new cell culture systems and model organisms, that are suited to the mechanistic investigation of the functions of these organelles in quiescent cells.
    Keywords:  ER; aging; lysosome; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.005
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