bims-mecosi 2021-11-21 papers

Issue of 2021–11–21
five papers selected by
Verena Kohler, Stockholm University

Prog Lipid Res. 2021 Nov 15. pii: S0163-7827(21)00057-6. [Epub ahead of print] 101141

Hello from the other side: Membrane contact of lipid droplets with other organelles and subsequent functional implications.

Rebekah Rakotonirina-Ricquebourg, Vítor Costa, Vitor Teixeira.

Lipid droplets (LDs) are ubiquitous organelles that play crucial roles in response to physiological and environmental cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). Increasing evidence suggests that distinct proteins and regulatory factors, which localize to membrane contact sites (MCS), are involved not only in interorganellar lipid exchange and transport, but also function in other important cellular processes, including autophagy, mitochondrial dynamics and inheritance, ion signaling and inter-regulation of these MCS. More and more tethers and molecular determinants are associated to MCS and to a diversity of cellular and pathophysiological processes, demonstrating the dynamics and importance of these junctions in health and disease. The conjugation of lipids with proteins in supramolecular complexes is known to be paramount for many biological processes, namely membrane biosynthesis, cell homeostasis, regulation of organelle division and biogenesis, and cell growth. Ultimately, this physical organization allows the contact sites to function as crucial metabolic hubs that control the occurrence of chemical reactions. This leads to biochemical and metabolite compartmentalization for the purposes of energetic efficiency and cellular homeostasis. In this review, we will focus on the structural and functional aspects of LD-organelle interactions and how they ensure signaling exchange and metabolites transfer between organelles.

Keywords: Interorganellar communication; Lipid droplet; Membrane biogenesis; Membrane contact sites; Metabolism; Molecular tether

DOI: https://doi.org/10.1016/j.plipres.2021.101141

Life Sci Alliance. 2022 Feb;pii: e202101278. [Epub ahead of print]5(2):

Serine palmitoyltransferase assembles at ER-mitochondria contact sites.

Mari J Aaltonen, Irina Alecu, Tim König, Steffany Al Bennett, Eric A Shoubridge.

The accumulation of sphingolipid species in the cell contributes to the development of obesity and neurological disease. However, the subcellular localization of sphingolipid-synthesizing enzymes is unclear, limiting the understanding of where and how these lipids accumulate inside the cell and why they are toxic. Here, we show that SPTLC2, a subunit of the serine palmitoyltransferase (SPT) complex, catalyzing the first step in de novo sphingolipid synthesis, localizes dually to the ER and the outer mitochondrial membrane. We demonstrate that mitochondrial SPTLC2 interacts and forms a complex in trans with the ER-localized SPT subunit SPTLC1. Loss of SPTLC2 prevents the synthesis of mitochondrial sphingolipids and protects from palmitate-induced mitochondrial toxicity, a process dependent on mitochondrial ceramides. Our results reveal the in trans assembly of an enzymatic complex at an organellar membrane contact site, providing novel insight into the localization of sphingolipid synthesis and the composition and function of ER-mitochondria contact sites.

DOI: https://doi.org/10.26508/lsa.202101278

Oxid Med Cell Longev. 2021 ;2021 8054817

The Mitochondrial-Associated Endoplasmic Reticulum Membrane and Its Role in Diabetic Nephropathy.

Lihua Ni, Cheng Yuan.

The mitochondrial-associated endoplasmic reticulum membrane (MAM) is located between the outer mitochondrial membrane and the endoplasmic reticulum membrane. The MAM is involved in a wide range of cellular functions, including calcium signaling, the division and fusion of mitochondria, endoplasmic reticulum stress, and the synthesis and transport of lipids. Recent studies have discovered that the MAM is involved in the pathogenesis of diabetic nephropathy (DN). In this article, we summarize the structure, function and role of the MAM in DN. We hope this study will provide clues and a theoretical basis for mechanistic and targeted drug research on DN.

DOI: https://doi.org/10.1155/2021/8054817

Nat Commun. 2021 Nov 19. 12(1): 6750

The autophagy protein ATG9A enables lipid mobilization from lipid droplets.

Elodie Mailler, Carlos M Guardia, Xiaofei Bai, Michal Jarnik, Chad D Williamson, Yan Li, Nunziata Maio, Andy Golden, Juan S Bonifacino.

The multispanning membrane protein ATG9A is a scramblase that flips phospholipids between the two membrane leaflets, thus contributing to the expansion of the phagophore membrane in the early stages of autophagy. Herein, we show that depletion of ATG9A does not only inhibit autophagy but also increases the size and/or number of lipid droplets in human cell lines and C. elegans. Moreover, ATG9A depletion blocks transfer of fatty acids from lipid droplets to mitochondria and, consequently, utilization of fatty acids in mitochondrial respiration. ATG9A localizes to vesicular-tubular clusters (VTCs) that are tightly associated with an ER subdomain enriched in another multispanning membrane scramblase, TMEM41B, and also in close proximity to phagophores, lipid droplets and mitochondria. These findings indicate that ATG9A plays a critical role in lipid mobilization from lipid droplets to autophagosomes and mitochondria, highlighting the importance of ATG9A in both autophagic and non-autophagic processes.

DOI: https://doi.org/10.1038/s41467-021-26999-x

FEBS J. 2021 Nov 16.

ATG2 and VPS13 proteins: Molecular highways transporting lipids to drive membrane expansion and organelle communication.

David G McEwan, Kevin Ryan.

Communication between organelles is an essential process that helps maintain cellular homeostasis and organelle contact sites have emerged recently as crucial mediators of this communication. The emergence of a class of molecular bridges that span the inter-organelle gaps has now been shown to direct the flow of lipid traffic from one lipid bilayer to another. One of the keys components of these molecular bridges is the presence of an N-terminal Chorein/VPS13 domain. This is an evolutionarily conserved domain present in multiple proteins within the endocytic and autophagy trafficking pathways. Herein, we discuss the current state-of-the-art of this class of proteins, focusing on the role of these lipid transporters in the autophagy and endocytic pathways. We discuss the recent biochemical and structural advances that have highlighted the essential role Chorein-N domain containing ATG2 proteins play in driving the formation of the autophagosome and how lipids are transported from the endoplasmic reticulum to the growing phagophore. We also consider the VPS13 proteins, their role in organelle contacts and the endocytic pathway and highlight how disease-causing mutations disrupt these contact sites. Finally, we open the door to discuss other Chorein_N domain containing proteins, for instance UHRF1BP1/1L, their role in disease and look towards prokaryote examples of Chorein_N-like domains. Taken together, recent advances have highlighted an exciting opportunity to delve deeper into inter-organelle communication and understand how lipids are transported between membrane bi-layers and how this process is disrupted in multiple diseases.

Keywords: ATG2; Autophagy; Chorein; Lipid transfer; UHRF1BP1; VPS13; endosome; organelle contacts

DOI: https://doi.org/10.1111/febs.16280