bims-lypmec 2023-04-09 papers

Issue of 2023‒04‒09
five papers selected by
Satoru Kobayashi
New York Institute of Technology

Nat Cell Biol. 2023 Apr 06.

A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins.

Anshu Bhattacharya, Rukmini Mukherjee, Santosh Kumar Kuncha, Melinda Elaine Brunstein, Rajeshwari Rathore, Stephan Junek, Christian Münch, Ivan Dikic.

Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential independent of lysosomal biogenesis and remain unaffected in cells depleted in TFEB and TFE3. We combined proximity-labelling-based proteomics, biochemistry and high-resolution microscopy to unravel a lysosomal membrane regeneration pathway that depends on ATG8, the lysosomal membrane protein LIMP2, the RAB7 GTPase-activating protein TBC1D15 and proteins required for autophagic lysosomal reformation, including dynamin-2, kinesin-5B and clathrin. Following lysosomal damage, LIMP2 acts as a lysophagy receptor to bind ATG8, which in turn recruits TBC1D15 to damaged membranes. TBC1D15 interacts with ATG8 proteins on damaged lysosomes and provides a scaffold to assemble and stabilize the autophagic lysosomal reformation machinery. This potentiates the formation of lysosomal tubules and subsequent dynamin-2-dependent scission. TBC1D15-mediated lysosome regeneration was also observed in a cell culture model of oxalate nephropathy.

DOI: https://doi.org/10.1038/s41556-023-01125-9

FEBS Open Bio. 2023 Apr 04.

Glycosphingolipids within membrane contact sites influence their function as signaling hubs in neurodegenerative diseases.

Jason Andrew Weesner, Ida Annunziata, Diantha van de Vlekkert, Alessandra d'Azzo.

Intracellular organelles carry out many of their functions by engaging in extensive inter-organellar communication through specialized membrane contact sites (MCSs) formed where two organelles tether to each other or to the plasma membrane without fusing. In recent years, these ubiquitous membrane structures have emerged as central signaling hubs that control a multitude of cellular pathways, ranging from lipid metabolism/transport to the exchange of metabolites and ions (i.e. Ca2+ ), and general organellar biogenesis. The functional crosstalk between juxtaposed membranes at MCSs relies on a defined composite of proteins and lipids that populate these microdomains in a dynamic fashion. This is particularly important in the nervous system, where alterations in the composition of MCSs have been shown to affect their functions and have been implicated in the pathogenesis of neurodegenerative diseases. In this review, we focus on the MCSs that are formed by the tethering of the endoplasmic reticulum (ER) to the mitochondria, the ER to the endo-lysosomes and the mitochondria to the lysosomes. We highlight how glycosphingolipids that are aberrantly processed/degraded and accumulate ectopically in intracellular membranes and the plasma membrane change the topology of MCSs, disrupting signaling pathways that lead to neuronal demise and neurodegeneration. In particular, we focus on neurodegenerative lysosomal storage diseases linked to altered glycosphingolipid catabolism.

DOI: https://doi.org/10.1002/2211-5463.13605

Cell Struct Funct. 2023 Apr 06.

Cell biology of protein-lipid conjugation.

Jun-Ichi Sakamaki, Noboru Mizushima.

Protein-lipid conjugation is a widespread modification involved in many biological processes. Various lipids, including fatty acids, isoprenoids, sterols, glycosylphosphatidylinositol, sphingolipids, and phospholipids, are covalently linked with proteins. These modifications direct proteins to intracellular membranes through the hydrophobic nature of lipids. Some of these membrane-binding processes are reversible through delipidation or by reducing the affinity to membranes. Many signaling molecules undergo lipid modification, and their membrane binding is important for proper signal transduction. The conjugation of proteins to lipids also influences the dynamics and function of organellar membranes. Dysregulation of lipidation has been associated with diseases such as neurodegenerative diseases. In this review, we first provide an overview of diverse forms of protein-lipid conjugation and then summarize the catalytic mechanisms, regulation, and roles of these modifications.Key words: Lipid, lipidation, membrane, organelle, protein modification.

Keywords: Lipid; lipidation; membrane; organelle; protein modification

DOI: https://doi.org/10.1247/csf.23016

FEBS Lett. 2023 Apr 04.

Vacuole membrane contact sites regulate liquid-ordered domain formation during glucose starvation.

Keiko Sakuragi, Philipp Schlarmann, Atsuko Ikeda, Kouichi Funato.

Liquid-ordered (Lo) membrane domains have been proposed to play important roles in a wide variety of biological processes, such as protein sorting and cell signaling. However, the mechanisms by which they are formed and maintained remain poorly understood. Lo domains are formed in the vacuolar membrane of yeast in response to glucose starvation. Here, we show that deletion of proteins which localize to vacuole membrane contact sites caused a marked decrease in the number of cells with Lo domains. In addition to Lo domain formation, autophagy is induced upon glucose starvation. However, deletion of core autophagy proteins did not inhibit Lo domain formation. Thus, we propose that vacuolar Lo domain formation during glucose restriction is regulated by membrane contact sites but not by autophagy.

Keywords: Lo domain; NVJ; autophagy; glucose starvation; vCLAMP

DOI: https://doi.org/10.1002/1873-3468.14621

J Physiol. 2023 Apr 03.

Acute exercise increases the contact between lipid droplets and mitochondria independently of obesity and type 2 diabetes.

Martin Eisemann de Almeida, Niels Ørtenblad, Maria Houborg Petersen, Ann-Sofie Nybøle Schjerning, Emil Kleis Wentorf, Kurt Jensen, Kurt Højlund, Joachim Nielsen.

Intramuscular lipid droplets (LDs) and mitochondria are essential organelles in cellular communication and metabolism, supporting local energy demands during muscle contractions. While insulin resistance impacts cellular functions and systems within the skeletal muscle, it remains unclear whether the interaction of LDs and mitochondria is affected by exercise and the role of obesity and type 2 diabetes. By employing transmission electron microscopy (TEM), we aimed to investigate the effects of 1-hour ergometry cycling on LD morphology, subcellular distribution, and mitochondrial contact in skeletal muscle fibres of patients with type 2 diabetes and glucose-tolerant lean and obese controls, matched for equal exercise intensities. Exercise did not change LD volumetric density, numerical density, profile size, or subcellular distribution. However, evaluated as the magnitude of inter-organelle contact, exercise increased the contact between LDs and mitochondria with no differences between the three groups. This effect was most profound in the subsarcolemmal space of type 1 muscle fibres, and here the absolute contact length increased on average from ∼275 to ∼420 nm. Furthermore, the absolute contact length before exercise (ranging from ∼140 to ∼430 nm) was positively associated with the fat oxidation rate during exercise. In conclusion, we showed that acute exercise did not mediate changes in the LD volume fractions, numbers, or size but increased the contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. These data suggest that the increased LD-mitochondrial contact with exercise is not disturbed in obesity or type 2 diabetes. KEY POINTS: Type 2 diabetes is associated with altered interactivity between lipid droplets (LDs) and mitochondria in the skeletal muscle. Physical contact between the surface of LDs and the surrounding mitochondrial network is considered favorable for fat oxidation. We show that one hour of acute exercise increases the length of contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. This contact length between LDs and mitochondria is not associated with a net decrease in the LD volumetric density after the acute exercise. However, it correlates with the fat oxidation rate during exercise. Our data establish that exercise mediates contact between LDs and the mitochondrial network and that this effect is not impaired in individuals with type 2 diabetes or obesity. Abstract figure legend One hour of acute exercise increases the absolute and relative measured contact between lipid droplets and mitochondria, irrespective of obesity or type 2 diabetes. Increases in lipid droplet-mitochondrial contact were not associated with changes in lipid droplet content (volume fractions) nor volumetric composition (number or size). The figure was designed using BioRender and resources from Flaticon.com. This article is protected by copyright. All rights reserved.

Keywords: LD-mitochondria contact; acute exercise; lipid droplets; skeletal muscle; transmission electron microscopy; type 2 diabetes

DOI: https://doi.org/10.1113/JP284386