bims-mecosi 2022-11-13 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2022–11–13
eight papers selected by
Verena Kohler, University of Graz

Nuclear Interactions: A Spotlight on Nuclear Mitochondrial Membrane Contact Sites.
Mitochondria-associated endoplasmic reticulum membranes and cardiac hypertrophy: Molecular mechanisms and therapeutic targets.
Systematic analysis of membrane contact sites in Saccharomyces cerevisiae uncovers modulators of cellular lipid distribution.
Ubiquitin-mediated mitochondrial regulation by MITOL/MARCHF5 at a glance.
--Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy.
Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress.
Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.
Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective.

Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221096217

Nuclear Interactions: A Spotlight on Nuclear Mitochondrial Membrane Contact Sites.

Jana Ovciarikova, Shikha Shikha, Lilach Sheiner.

  Membrane contact sites (MCS) are critical for cellular functions of eukaryotes, as they enable communication and exchange between organelles. Research over the last decade unravelled the function and composition of MCS between a variety of organelles including mitochondria, ER, plasma membrane, lysosomes, lipid droplets, peroxisome and endosome, to name a few. In fact, MCS are found between any pair of organelles studied to date, with common functions including lipid exchange, calcium signalling and organelle positioning in the cell. Work in the past year has started addressing the composition and function of nuclear-mitochondrial MCS. Tether components mediating these contacts in yeast have been identified via comprehensive phenotypic screens, which also revealed a possible link between this contact and phosphatidylcholine metabolism. In human cells, and in the protozoan parasites causing malaria, proximity between these organelles is proposed to promote cell survival via a mitochondrial retrograde response. These pioneering studies should inspire the field to explore what cellular processes depend on the exchange between the nucleus and the mitochondrion, given that they play such central roles in cell biology.

Keywords:  membrane contact sites; mitochondrion (mitochondria); nucleus; parasite

DOI:  https://doi.org/10.1177/25152564221096217
Front Cardiovasc Med. 2022 ;9 1015722

Mitochondria-associated endoplasmic reticulum membranes and cardiac hypertrophy: Molecular mechanisms and therapeutic targets.

Yi Luan, Yage Jin, Pengjie Zhang, Hongqiang Li, Yang Yang.

  Cardiac hypertrophy has been shown to compensate for cardiac performance and improve ventricular wall tension as well as oxygen consumption. This compensatory response results in several heart diseases, which include ischemia disease, hypertension, heart failure, and valvular disease. Although the pathogenesis of cardiac hypertrophy remains complicated, previous data show that dysfunction of the mitochondria and endoplasmic reticulum (ER) mediates the progression of cardiac hypertrophy. The interaction between the mitochondria and ER is mediated by mitochondria-associated ER membranes (MAMs), which play an important role in the pathology of cardiac hypertrophy. The function of MAMs has mainly been associated with calcium transfer, lipid synthesis, autophagy, and reactive oxygen species (ROS). In this review, we discuss key MAMs-associated proteins and their functions in cardiovascular system and define their roles in the progression of cardiac hypertrophy. In addition, we demonstrate that MAMs is a potential therapeutic target in the treatment of cardiac hypertrophy.

Keywords:  MAMs-associated proteins; cardiac hypertrophy; cardiovascular system; mitochondria-associated ER membranes (MAMs); therapeutic targets

DOI:  https://doi.org/10.3389/fcvm.2022.1015722
Elife. 2022 Nov 10. pii: e74602. [Epub ahead of print]11

Systematic analysis of membrane contact sites in Saccharomyces cerevisiae uncovers modulators of cellular lipid distribution.

Inês Gomes Castro, Shawn P Shortill, Samantha Katarzyna Dziurdzik, Angela Cadou, Suriakarthiga Ganesan, Rosario Valenti, Yotam David, Michael Davey, Carsten Mattes, Ffion B Thomas, Reut Ester Avraham, Hadar Meyer, Amir Fadel, Emma J Fenech, Robert Ernst, Vanina Zaremberg, Tim P Levine, Christopher Stefan, Elizabeth Conibear, Maya Schuldiner.

  Actively maintained close appositions between organelle membranes, also known as contact sites, enable the efficient transfer of biomolecules between cellular compartments. Several such sites have been described as well as their tethering machineries. Despite these advances we are still far from a comprehensive understanding of the function and regulation of most contact sites. To systematically characterize contact site proteomes, we established a high-throughput screening approach in Saccharomyces cerevisiae based on co-localization imaging. We imaged split fluorescence reporters for six different contact sites, several of which are poorly characterized, on the background of 1165 strains expressing a mCherry-tagged yeast protein that has a cellular punctate distribution (a hallmark of contact sites), under regulation of the strong TEF2 promoter. By scoring both co-localization events and effects on reporter size and abundance, we discovered over 100 new potential contact site residents and effectors in yeast. Focusing on several of the newly identified residents, we identified three homologs of Vps13 and Atg2 that are residents of multiple contact sites. These proteins share their lipid transport domain, thus expanding this family of lipid transporters. Analysis of another candidate, Ypr097w, which we now call Lec1 (Lipid-droplet Ergosterol Cortex 1), revealed that this previously uncharacterized protein dynamically shifts between lipid droplets and the cell cortex, and plays a role in regulation of ergosterol distribution in the cell. Overall, our analysis expands the universe of contact site residents and effectors and creates a rich database to mine for new functions, tethers, and regulators.

Keywords:  S. cerevisiae; YPR097W; cell biology; contact sites; lec1; lipid droplets; vps13 family

DOI:  https://doi.org/10.7554/eLife.74602
J Biochem. 2022 Nov 08. pii: mvac092. [Epub ahead of print]

Ubiquitin-mediated mitochondrial regulation by MITOL/MARCHF5 at a glance.

Shun Nagashima, Naoki Ito, Isshin Shiiba, Hiroki Shimura, Shigeru Yanagi.

  Mitochondria are involved in various cellular processes, such as energy production, inflammatory responses, and cell death. Mitochondrial dysfunction is associated with many age-related diseases, including neurological disorders and heart failure. Mitochondrial quality is strictly maintained by mitochondrial dynamics linked to an adequate supply of phospholipids and other substances from the endoplasmic reticulum (ER). The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 is responsible for mitochondrial quality control through the regulation of mitochondrial dynamics, formation of mitochondria-ER contacts, and mitophagy. MITOL deficiency has been shown to impair mitochondrial function, cause an excessive inflammatory response, and increase vulnerability to stress, resulting in the exacerbation of the disease. In this study, we overview the ubiquitin-mediated regulation of mitochondrial function by MITOL and the relationship between MITOL and diseases.

Keywords:  MITOL/MARCHF5; mitochondria; mitochondria-ER contacts; mitochondrial dynamics; ubiquitin

DOI:  https://doi.org/10.1093/jb/mvac092
Autophagy. 2022 Nov 10. 1-20

--Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy.

Sabrina Chumpen Ramirez, Rubén Gómez-Sánchez, Pauline Verlhac, Ralph Hardenberg, Eleonora Margheritis, Katia Cosentino, Fulvio Reggiori, Christian Ungermann.

  During macroautophagy/autophagy, precursor cisterna known as phagophores expand and sequester portions of the cytoplasm and/or organelles, and subsequently close resulting in double-membrane transport vesicles called autophagosomes. Autophagosomes fuse with lysosomes/vacuoles to allow the degradation and recycling of their cargoes. We previously showed that sequential binding of yeast Atg2 and Atg18 to Atg9, the only conserved transmembrane protein in autophagy, at the extremities of the phagophore mediates the establishment of membrane contact sites between the phagophore and the endoplasmic reticulum. As the Atg2-Atg18 complex transfers lipids between adjacent membranes in vitro, it has been postulated that this activity and the scramblase activity of the trimers formed by Atg9 are required for the phagophore expansion. Here, we present evidence that Atg9 indeed promotes Atg2-Atg18 complex-mediated lipid transfer in vitro, although this is not the only requirement for its function in vivo. In particular, we show that Atg9 function is dramatically compromised by a F627A mutation within the conserved interface between the transmembrane domains of the Atg9 monomers. Although Atg9F627A self-interacts and binds to the Atg2-Atg18 complex, the F627A mutation blocks the phagophore expansion and thus autophagy progression. This phenotype is conserved because the corresponding human ATG9A mutant severely impairs autophagy as well. Importantly, Atg9F627A has identical scramblase activity in vitro like Atg9, and as with the wild-type protein enhances Atg2-Atg18-mediated lipid transfer. Collectively, our data reveal that interactions of Atg9 trimers via their transmembrane segments play a key role in phagophore expansion beyond Atg9's role as a lipid scramblase.Abbreviations: BafA1: bafilomycin A1; Cvt: cytoplasm-to-vacuole targeting; Cryo-EM: cryo-electron microscopy; ER: endoplasmic reticulum; GFP: green fluorescent protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCS: membrane contact site; NBD-PE: N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine; PAS: phagophore assembly site; PE: phosphatidylethanolamine; prApe1: precursor Ape1; PtdIns3P: phosphatidylinositol-3-phosphate; SLB: supported lipid bilayer; SUV: small unilamellar vesicle; TMD: transmembrane domain; WT: wild type.

Keywords:  Autophagosome; lipid transfer; membrane contact site; phagophore; scramblase

DOI:  https://doi.org/10.1080/15548627.2022.2136340
iScience. 2022 Nov 18. 25(11): 105362

Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress.

Yuriko Kakimoto-Takeda, Rieko Kojima, Hiroya Shiino, Manatsu Shinmyo, Kazuo Kurokawa, Akihiko Nakano, Toshiya Endo, Yasushi Tamura.

  In yeast, ERMES, which mediates phospholipid transport between the ER and mitochondria, forms a limited number of oligomeric clusters at ER-mitochondria contact sites in a cell. Although the number of the ERMES clusters appears to be regulated to maintain proper inter-organelle phospholipid trafficking, its underlying mechanism and physiological relevance remain poorly understood. Here, we show that mitochondrial dynamics control the number of ERMES clusters. Moreover, we find that ER stress causes dissociation of the ERMES clusters independently of Ire1 and Hac1, canonical ER-stress response pathway components, leading to a delay in the phospholipid transport from the ER to mitochondria. Our biochemical and genetic analyses strongly suggest that the impaired phospholipid transport contributes to phospholipid accumulation in the ER, expanding the ER for ER stress attenuation. We thus propose that the ERMES dissociation constitutes an overlooked pathway of the ER stress response that operates in addition to the canonical Ire1/Hac1-dependent pathway.

Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2022.105362
Nat Commun. 2022 Nov 09. 13(1): 6779

Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.

Máté Katona, Ádám Bartók, Zuzana Nichtova, György Csordás, Elena Berezhnaya, David Weaver, Arijita Ghosh, Péter Várnai, David I Yule, György Hajnóczky.

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when 'parked', mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.

DOI: https://doi.org/10.1038/s41467-022-34365-8
Biomolecules. 2022 Oct 29. pii: 1595. [Epub ahead of print]12(11):

Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective.

Jara Tabitha Hees, Angelika Bettina Harbauer.

  Neurons critically depend on mitochondria for ATP production and Ca2+ buffering. They are highly compartmentalized cells and therefore a finely tuned mitochondrial network constantly adapting to the local requirements is necessary. For neuronal maintenance, old or damaged mitochondria need to be degraded, while the functional mitochondrial pool needs to be replenished with freshly synthesized components. Mitochondrial biogenesis is known to be primarily regulated via the PGC-1α-NRF1/2-TFAM pathway at the transcriptional level. However, while transcriptional regulation of mitochondrial genes can change the global mitochondrial content in neurons, it does not explain how a morphologically complex cell such as a neuron adapts to local differences in mitochondrial demand. In this review, we discuss regulatory mechanisms controlling mitochondrial biogenesis thereby making a case for differential regulation at the transcriptional and translational level. In neurons, additional regulation can occur due to the axonal localization of mRNAs encoding mitochondrial proteins. Hitchhiking of mRNAs on organelles including mitochondria as well as contact site formation between mitochondria and endolysosomes are required for local mitochondrial biogenesis in axons linking defects in any of these organelles to the mitochondrial dysfunction seen in various neurological disorders.

Keywords:  AMPK; PGC-1α; insulin; mTORC1; mitochondrial biogenesis; neurons; transcription; translation

DOI:  https://doi.org/10.3390/biom12111595