Patrick Rockenfeller
Christopher T. Beh
Alexandre Toulmay4- 1Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Witten, Germany
- 2Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
- 3Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, BC, Canada
- 4National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
Editorial on the Research Topic
Lipids and Membrane Contacts in Yeast – Structure, Functional Aspects and Implications on Ageing, Cell Death and Autophagy
Membrane contact sites (MCSs) are junctions between different intracellular organelles that promote inter-membrane exchange and regulatory coordination. As sites enriched in lipid transfer proteins (LTPs) and small solute transporters, MCSs confer the “non-vesicular” direct exchange of lipids and small solutes (e.g., Ca2+) between closely apposed membranes, which act in parallel to canonical transport pathways for proteins and membrane components via vesicle trafficking (Phillips and Voeltz, 2016; Prinz et al., 2020). In fact, in the absence of vesicle transport some insoluble lipids such as ceramide, sterols, and specific phospholipids still move between cellular compartments unimpeded (Urbani and Simoni, 1990; Baumann et al., 2005; Hanada et al., 2009). In addition, some organelles, such as mitochondria and lipid droplets, are not even connected to the vesicular trafficking pathway suggesting that lipids move from and to these organelles only by non-vesicular means.
Although MCSs were originally identified almost 70 years ago (Bernhard et al., 1952; Bernhard and Rouiller, 1956; Porter and Palade, 1957), it has been within the last decade that many MCS proteins have been identified and their structural properties have been determined (Fernández-Busnadiego et al., 2015; Gallo et al., 2016; Reinisch and De Camilli, 2016; Hoffmann et al., 2019). Lagging behind this understanding, however, the functional roles of MCSs in the regulation of cell growth and physiology are still poorly defined.
Exploiting the molecular genetic tools available using Saccharomyces cerevisiae, recent discoveries detailing mechanisms of yeast MCS activities have focused on their regulatory significance in metabolic homeostasis (Henne et al., 2015; Jeong et al., 2017; González Montoro et al., 2018). MCS-dependent coordination of metabolism between specific membranes regulates organelle biogenesis, cellular quiescence, intracellular lipid and calcium mobilization/storage, and basic cellular bioenergetics (Kaufman and Malhotra, 2014; Herrera-Cruz and Simmen, 2017; Stefan et al., 2017; Farré et al., 2019). Given that many molecular components required for yeast MCSs share evolutionary conservation with homologues in higher eukaryotes, it is unsurprising that these studies in yeast provide valuable insights into MCS functions implicated in human disease (Rockenfeller and Gourlay, 2018; Prinz et al., 2020; Herker et al., 2021).
Still, many roadblocks remain in the MCS field, which need to be addressed in future investigations. This includes visualization of MCSs and proteins localized to MCSs, analysis of MCS formation dynamics, purification of organelle membranes and detection of lipid trafficking in live cells. The questions confronting current investigations into MCSs are: 1) How do the structural attributes of MCS proteins regulate lipid metabolism? 2) How does bulk lipid trafficking—in particular of phospholipids—work, and how is this regulated? 3) What growth conditions or genetic programs control the metabolic changes conferred by MCSs? And given the links between MCSs and disease pathology: 4) Do MCSs provide pharmacological targets for therapies combating the ever-increasing list of MCS-related disorders?
In this Research Topic we focus on functional aspects regulated through MCSs. These functional aspects impact inter-organelle communication, organelle structure, organelle inheritance and biogenesis, lipid and protein traffic, but also encompass cellular processes such as autophagy, membrane stress responses, cell death and ageing. Our knowledge about MCSs has exponentially increased throughout the past few years during which we have come to appreciate the importance of MCSs as platforms for general subcellular organization that dynamically coordinate multi-organelle processes. This research topic includes six review articles and one original research article that highlight recent advances in the field of MCS research, and describe the complex functional connections between lipid trafficking, metabolite channeling, autophagy, cell death and quiescence.
In the review article “A Unique Junctional Interface at Contact Sites Between the Endoplasmic Reticulum and Lipid Droplets” Choudhary and Schneiter summarize the current knowledge on ER-lipid droplet (LD) contacts, but also LD contacts with mitochondria and peroxisomes. In particular, this article discusses the function of specific LD-contact site components that generate the unique membrane interface that drives LD formation, lipogenesis and lipolysis. Emphasizing the cellular need to coordinate cellular lipid homeostasis between organelles, the authors also consider the roles of membrane LD-mitochondria and LD-peroxisome tethers, which support unique metabolic chemistries that are spatially segregated with cells. Because cellular bioenergetics and metabolism depends on LD interactions with these organelle membranes, the contribution of LD contacts on health and disease is also discussed.
Whereas Choudhary and Schneiter focus on LD biogenesis, Renne and Hariri concentrate on LD contacts with other organelles and their roles in fatty acid (FA) metabolism and trafficking. Their review article, “Lipid Droplet-Organelle Contact Sites as Hubs for Fatty Acid Metabolism, Trafficking, and Metabolic Channeling,” describe mechanisms by which LD contacts impact FA metabolism, including catabolism, synthesis, desaturation, elongation, and incorporation of FAs into complex lipids. In particular, the authors give insight into the importance of LD–ER contacts for metabolic channeling of FAs into LDs, which is an important requirement for lipid storage. They further discuss the function of LD contacts with peroxisomes and mitochondria for FA-beta-oxidation, and the roles of LD-vacuole contact sites for FA storage and mobilization.
In the review article “Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels,” Pascal Egea describes mechanistic features of lipid transfer proteins (LTPs) at the heart of MCSs. Based on structural and functional properties, LTP mechanisms are categorized into 1) diffusion, 2) sliding and 3) bridging-based. These mechanisms are discussed in depth as illustrated by the structural attributes of Ups1/Mdm35, ERMES, and other LTPs.
A particular focus on peroxisomal MCSs is presented in the mini-review “Peroxisomal Membrane Contact Sites in Yeasts” by Amit Joshi. Although these peroxisomal MCS include those with LDs as reviewed by Choudhary and Schneiter and Renne and Hariri, this article further extends to peroxisomal contacts with the ER, mitochondria, vacuole and plasma membrane. The author not only describes the structural features of these peroxisomal MCSs but also discusses functional aspects of peroxisomal MCSs important during processes such as peroxisome biogenesis.
Lenoir et al. also contribute to this special issue with their review article “Transport Pathways That Contribute to the Cellular Distribution of Phosphatidylserine”. The authors give a comprehensive overview of the current understanding on phosphatidylserine (PS) biosynthesis and the maintenance of its distribution in cellular membranes, including lateral distribution within bilayers. They discuss the intracellular trafficking of PS between membranes by different LTPs at ER contact sites with mitochondria, the plasma membrane, and with the autophagy isolation membrane. PS exchange between the two layers of the same membrane by flippases, and scramblases is also discussed.
The review article “Membrane-Interacting Antifungal Peptides” by Struyfs et al. takes a different viewpoint on lipid membranes. Here the authors focus on the membrane interaction of antimicrobial peptides (AMPs), in particular antimycotic peptides. Because fungal infections are on the rise worldwide, this article provides a fresh perspective on the growing knowledge on lipid membranes, as well as MCSs and their regulation, that can be exploited for medical and pharmacological purposes. In particular, the authors describe AMP structures and mechanisms allowing for specific fungal membrane interactions linked to programmed cell death, autophagy, mitochondrial dysfunction and MCSs.
In the original research article “Sterol metabolism differentially contributes to maintenance and exit of quiescence” Peselj et al. report on the role of lipids in the regulation of quiescence. They investigate the storage and consumption of neutral lipids upon glucose or phosphate starvation. The authors find that upon glucose exhaustion, LDs were degraded by lipophagy. Upon nitrogen exhaustion, however, cells exhibit a nucleus-vacuole junction expansion and accumulate LDs on the vacuole surface. Significantly, the formation of steryl esters and their hydrolysis and mobilization from LDs is critical for survival of phosphate starvation but not during glucose starvation. They conclude that the mechanism by which neutral lipid homeostasis adapts to both support quiescence and to exit from quiescence is specifically dependent on the limiting nutrient.
Altogether, this compilation delivers a focused picture of yeast MCSs and their impact on lipid homeostasis and other functional contributions to cell ageing, cell death, and autophagy.
Author Contributions
PR and CTB wrote the first draft of the editorial. AT wrote sections of the editorial. All authors contributed to manuscript revision, read, and approved the submitted version.
Funding
PR is supported by the “NRW Rückkehr Programm” from the Ministry of Culture and Science of the German State of North Rhine-Westphalia. CB is supported by “Discovery Grant” and “Accelerator Supplement” from the Natural Sciences and Engineering Research Council (NSERC) of Canada. AT is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kindey Diseases.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
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References
Baumann, N. A., Sullivan, D. P., Ohvo-Rekilä, H., Simonot, C., Pottekat, A., Klaassen, Z., et al. (2005). Transport of Newly Synthesized Sterol to the Sterol-Enriched Plasma Membrane Occurs via Nonvesicular Equilibration. Biochemistry 44, 5816–5826. doi:10.1021/bi048296z
Bernhard, W., Haguenau, F., Gautier, A., and Oberling, C. (1952). La structure submicroscopique des elements basophiles cytoplasmiques dans le foie, le pancreas et les glandes salivaires. Z. Zellforschung 37, 281–300. doi:10.1007/bf00343816
Bernhard, W., and Rouiller, C. (1956). Close Topographical Relationship between Mitochondria and Ergastoplasm of Liver Cells in a Definite Phase of Cellular Activity. J. Biophys. Biochem. Cytol. 2, 73–78. doi:10.1083/jcb.2.4.73
Farré, J. C., Mahalingam, S. S., Proietto, M., and Subramani, S. (2019). Peroxisome Biogenesis, Membrane Contact Sites, and Quality Control. EMBO Rep. 20, e46864. doi:10.15252/embr.201846864
Fernández-Busnadiego, R., Saheki, Y., and De Camilli, P. (2015). Three-dimensional Architecture of Extended Synaptotagmin-Mediated Endoplasmic Reticulum-Plasma Membrane Contact Sites. Proc. Natl. Acad. Sci. U.S.A. 112, E2004–E2013. doi:10.1073/pnas.1503191112
Gallo, A., Vannier, C., and Galli, T. (2016). Endoplasmic Reticulum-Plasma Membrane Associations: Structures and Functions. Annu. Rev. Cel Dev. Biol. 32, 279–301. doi:10.1146/annurev-cellbio-111315-125024
González Montoro, A., Auffarth, K., Hönscher, C., Bohnert, M., Becker, T., Warscheid, B., et al. (2018). Vps39 Interacts with Tom40 to Establish One of Two Functionally Distinct Vacuole-Mitochondria Contact Sites. Dev. Cel 45, 621–636.e7. doi:10.1016/j.devcel.2018.05.011
Hanada, K., Kumagai, K., Tomishige, N., and Yamaji, T. (2009). CERT-mediated Trafficking of Ceramide. Biochim. Biophys. Acta (Bba) - Mol. Cel Biol. Lipids 1791, 684–691. doi:10.1016/j.bbalip.2009.01.006
Henne, W. M., Zhu, L., Balogi, Z., Stefan, C., Pleiss, J. A., and Emr, S. D. (2015). Mdm1/Snx13 Is a Novel ER-Endolysosomal Interorganelle Tethering Protein. J. Cel Biol 210, 541–551. doi:10.1083/jcb.201503088
Herker, E., Vieyres, G., Beller, M., Krahmer, N., and Bohnert, M. (2021). Lipid Droplet Contact Sites in Health and Disease. Trends Cel Biol. 31, 345–358. doi:10.1016/j.tcb.2021.01.004
Herrera-Cruz, M. S., and Simmen, T. (2017). Of Yeast, Mice and Men: MAMs Come in Two Flavors. Biol. Direct 12, 3. doi:10.1186/s13062-017-0174-5
Hoffmann, P. C., Bharat, T. A. M., Wozny, M. R., Boulanger, J., Miller, E. A., and Kukulski, W. (2019). Tricalbins Contribute to Cellular Lipid Flux and Form Curved ER-PM Contacts that Are Bridged by Rod-Shaped Structures. Dev. Cel 51, 488–502.e8. doi:10.1016/j.devcel.2019.09.019
Jeong, H., Park, J., Jun, Y., and Lee, C. (2017). Crystal Structures of Mmm1 and Mdm12-Mmm1 Reveal Mechanistic Insight into Phospholipid Trafficking at ER-Mitochondria Contact Sites. Proc. Natl. Acad. Sci. U.S.A. 114, E9502–E9511. doi:10.1073/pnas.1715592114
Kaufman, R. J., and Malhotra, J. D. (2014). Calcium Trafficking Integrates Endoplasmic Reticulum Function with Mitochondrial Bioenergetics. Biochim. Biophys. Acta (Bba) - Mol. Cel Res. 1843, 2233–2239. doi:10.1016/j.bbamcr.2014.03.022
Phillips, M. J., and Voeltz, G. K. (2016). Structure and Function of ER Membrane Contact Sites with Other Organelles. Nat. Rev. Mol. Cel Biol 17, 69–82. doi:10.1038/nrm.2015.8
Porter, K. R., and Palade, G. E. (1957). Studies on the Endoplasmic Reticulum. J. Biophys. Biochem. Cytol. 3, 269–300. doi:10.1083/jcb.3.2.269
Prinz, W. A., Toulmay, A., and Balla, T. (2020). The Functional Universe of Membrane Contact Sites. Nat. Rev. Mol. Cel Biol. 21, 7–24. doi:10.1038/s41580-019-0180-9
Reinisch, K. M., and De Camilli, P. (2016). SMP-domain Proteins at Membrane Contact Sites: Structure and Function. Biochim. Biophys. Acta (Bba) - Mol. Cel Biol. Lipids 1861, 924–927. doi:10.1016/j.bbalip.2015.12.003
Rockenfeller, P., and Gourlay, C. W. (2018). Lipotoxicty in Yeast: a Focus on Plasma Membrane Signalling and Membrane Contact Sites. FEMS Yeast Res. 18. doi:10.1093/femsyr/foy034
Stefan, C. J., Trimble, W. S., Grinstein, S., Drin, G., Reinisch, K., De Camilli, P., et al. (2017). Membrane Dynamics and Organelle Biogenesis-Lipid Pipelines and Vesicular Carriers. BMC Biol. 15, 102. doi:10.1186/s12915-017-0432-0
Keywords: membrane contact site (MCS), lipid droplet (LD), lipid trafficking and metabolism, autophagy, cell death
Citation: Rockenfeller P, Beh CT and Toulmay A (2022) Editorial: Lipids and Membrane Contacts in Yeast—Structure, Functional Aspects and Implications on Ageing, Cell Death and Autophagy. Front. Cell Dev. Biol. 10:881666. doi: 10.3389/fcell.2022.881666
Received: 22 February 2022; Accepted: 28 March 2022;
Published: 12 April 2022.
Edited by:
Vladimir Lupashin, University of Arkansas for Medical Sciences, United StatesReviewed by:
Rutilio A. Fratti, University of Illinois at Urbana-Champaign, United StatesCopyright © 2022 Rockenfeller, Beh and Toulmay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Patrick Rockenfeller, cGF0cmljay5yb2NrZW5mZWxsZXJAdW5pLXdoLmRl