bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024‒06‒23
eight papers selected by
Verena Kohler, Umeå University
  1. PDZD8-FKBP8 tethering complex at ER-mitochondria contact sites regulates mitochondrial complexity.
  2. Role of lipids in interorganelle communication.
  3. Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.
  4. Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.
  5. MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
  6. A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.
  7. Mitochondrial biology: Unique membrane remodeling from the matrix.
  8. Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C.
  1. bioRxiv. 2024 Jun 03. pii: 2023.08.22.554218. [Epub ahead of print]
    PDZD8-FKBP8 tethering complex at ER-mitochondria contact sites regulates mitochondrial complexity.
    Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.
      Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identified the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-Electron Microscopy (Cryo-EM) tomography, and correlative light-EM (CLEM). Single molecule tracking revealed highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and capture at MERCS. Overexpression of FKBP8 was sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrated their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.
    DOI:  https://doi.org/10.1101/2023.08.22.554218
  2. Trends Cell Biol. 2024 Jun 11. pii: S0962-8924(24)00095-3. [Epub ahead of print]
    Role of lipids in interorganelle communication.
    Neuza Domingues, Joana Pires, Ira Milosevic, Nuno Raimundo.
      Cell homeostasis and function rely on well-orchestrated communication between different organelles. This communication is ensured by signaling pathways and membrane contact sites between organelles. Many players involved in organelle crosstalk have been identified, predominantly proteins and ions. The role of lipids in interorganelle communication remains poorly understood. With the development and broader availability of methods to quantify lipids, as well as improved spatiotemporal resolution in detecting different lipid species, the contribution of lipids to organelle interactions starts to be evident. However, the specific roles of various lipid molecules in intracellular communication remain to be studied systematically. We summarize new insights in the interorganelle communication field from the perspective of organelles and discuss the roles played by lipids in these complex processes.
    Keywords:  endoplasmic reticulum; interorganelle communication; lipids; lysosomes; mitochondria; nucleus; peroxisomes
    DOI:  https://doi.org/10.1016/j.tcb.2024.04.008
  3. Nature. 2024 Jun 12.
    Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.
    Bo Gong, Jake D Johnston, Alexander Thiemicke, Alex de Marco, Tobias Meyer.
      Directed cell migration is driven by the front-back polarization of intracellular signalling1-3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4-6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7-9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum-plasma membrane (ER-PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER-PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER-PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER-PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front-back ER-PM contact gradient. Together, our study suggests that the structural polarity mediated by ER-PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.
    DOI:  https://doi.org/10.1038/s41586-024-07527-5
  4. Nat Commun. 2024 Jun 18. 15(1): 5199
    Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.
    Jia-Rui Zhang, Shi-Yu Shen, Meng-Ying Zhai, Zu-Qi Shen, Wei Li, Ling-Feng Liang, Shu-Yuan Yin, Qiu-Qin Han, Bing Li, Yu-Qiu Zhang, Jin Yu.
      Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.
    DOI:  https://doi.org/10.1038/s41467-024-49597-z
  5. iScience. 2024 Jun 21. 27(6): 109994
    MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
    Atul Kumar, Delfina Larrea, Maria Elena Pero, Paola Infante, Marilisa Conenna, Grace J Shin, Vincent Van Elias, Wesley B Grueber, Lucia Di Marcotullio, Estela Area-Gomez, Francesca Bartolini.
      Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.
    Keywords:  Cell biology; Lipidomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109994
  6. Nat Commun. 2024 Jun 15. 15(1): 5119
    A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.
    Deborah Mesa, Elisa Barbieri, Andrea Raimondi, Stefano Freddi, Giorgia Miloro, Gorana Jendrisek, Giusi Caldieri, Micaela Quarto, Irene Schiano Lomoriello, Maria Grazia Malabarba, Arianna Bresci, Francesco Manetti, Federico Vernuccio, Hind Abdo, Giorgio Scita, Letizia Lanzetti, Dario Polli, Carlo Tacchetti, Paolo Pinton, Massimo Bonora, Pier Paolo Di Fiore, Sara Sigismund.
      One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET.
    DOI:  https://doi.org/10.1038/s41467-024-49543-z
  7. Curr Biol. 2024 Jun 17. pii: S0960-9822(24)00608-0. [Epub ahead of print]34(12): R581-R583
    Mitochondrial biology: Unique membrane remodeling from the matrix.
    Jason A Mears.
      A new study reports the identification of a fission yeast dynamin superfamily protein, Mmc1, that self-assembles on the matrix side of the inner mitochondrial membrane and interacts with subunits of the mitochondrial contact site and cristae organizing system to maintain cristae architecture.
    DOI:  https://doi.org/10.1016/j.cub.2024.05.010
  8. bioRxiv. 2024 Jun 08. pii: 2024.06.08.598070. [Epub ahead of print]
    Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C.
    Xinbo Wang, Peng Xu, Amanda Bentley-DeSousa, William Hancock-Cerutti, Shujun Cai, Benjamin T Johnson, Francesca Tonelli, Gabriel Talaia, Dario R Alessi, Shawn M Ferguson, Pietro De Camilli.
      Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires release of a brake, most likely an intramolecular interaction within VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the putative role of VPS13 proteins in bulk lipid transport, these findings suggest lipid delivery to lysosomes by VPS13C is part of an early response to lysosome damage.
    DOI:  https://doi.org/10.1101/2024.06.08.598070
This page is being maintained by Thomas Krichel. It was last updated on 2024‒06‒25 at 6:44.