bims-mecosi 2023-04-09 papers

Issue of 2023–04–09
eight papers selected by
Verena Kohler, University of Graz

Front Cardiovasc Med. 2023 ;10 1168152

Editorial: Recent advances in mitochondria-associated endoplasmic reticulum membranes (MAMs) in heart-related diseases.

Keywords: CVDs (Cardio vascular diseases); ROS; endoplasmic recticulum; mitochondria; mitochondria-associated endoplasmic reticulum membranes

DOI: https://doi.org/10.3389/fcvm.2023.1168152

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

Ageing Res Rev. 2023 Mar 31. pii: S1568-1637(23)00079-X. [Epub ahead of print]87 101920

Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases.

Qiangqiang He, Meiyu Qu, Tingyu Shen, Jiakun Su, Yana Xu, Chengyun Xu, Muhammad Qasim Barkat, Jibao Cai, Haibin Zhu, Ling-Hui Zeng, Ximei Wu.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic coupling structures between mitochondria and the endoplasmic reticulum (ER). As a new subcellular structure, MAMs combine the two critical organelle functions. Mitochondria and the ER could regulate each other via MAMs. MAMs are involved in calcium (Ca2+) homeostasis, autophagy, ER stress, lipid metabolism, etc. Researchers have found that MAMs are closely related to metabolic syndrome and neurodegenerative diseases (NDs). The formation of MAMs and their functions depend on specific proteins. Numerous protein enrichments, such as the IP3R-Grp75-VDAC complex, constitute MAMs. The changes in these proteins govern the interaction between mitochondria and the ER; they also affect the biological functions of MAMs. S-palmitoylation is a reversible protein post-translational modification (PTM) that mainly occurs on protein cysteine residues. More and more studies have shown that the S-palmitoylation of proteins is closely related to their membrane localization. Here, we first briefly describe the composition and function of MAMs, reviewing the component and biological roles of MAMs mediated by S-palmitoylation, elaborating on S-palmitoylated proteins in Ca2+ flux, lipid rafts, and so on. We try to provide new insight into the molecular basis of MAMs-related diseases, mainly NDs. Finally, we propose potential drug compounds targeting S-palmitoylation.

Keywords: Ca(2+); Lipid rafts; MAMs; Neurodegenerative diseases; S-palmitoylation

DOI: https://doi.org/10.1016/j.arr.2023.101920

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

Pharmacol Res. 2023 Apr 05. pii: S1043-6618(23)00117-2. [Epub ahead of print] 106761

Mitochondria associated ER membrane and cerebral ischemia: molecular mechanisms and therapeutic strategies.

Rui-Qi Jiang, Qi-Qi Li, Rui Sheng.

Endoplasmic reticulum (ER) and mitochondria are two important organelles that are highly dynamic in mammalian cells. The physical connection between them is mitochondria associated ER membranes (MAM). In recent years, studies on endoplasmic reticulum and mitochondria have shifted from independent division to association and comparison, especially MAM has gradually become a research hotspot. MAM connects the two organelles, not only to maintain their independent structure and function, but also to promote metabolism and signal transduction between them. This paper reviews the morphological structure and protein localization of MAM, and briefly analyzes the functions of MAM in regulating Ca2+ transport, lipid synthesis, mitochondrial fusion and fission, endoplasmic reticulum stress and oxidative stress, autophagy and inflammation. Since ER stress and mitochondrial dysfunction are important pathological events in neurological diseases including ischemic stroke, MAM is likely to play an important role in cerebral ischemia by regulating the signaling of the two organelles and the crosstalk of the two pathological events.

Keywords: Ca(2+); Mitochondria associated ER membranes (MAM); autophagy; cerebral ischemia

DOI: https://doi.org/10.1016/j.phrs.2023.106761

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

ER membrane contact sites: key platforms for biogenesis of RNA-containing extracellular vesicles.

Bahnisikha Barman, T Renee Dawson, Alissa M Weaver.

The mechanisms by which cytoplasmic cargoes such as RNAs are incorporated into extracellular vesicles (EVs) are poorly understood. In a recent article published in Developmental Cell, we describe a novel function of endoplasmic reticulum membrane contact sites (ER MCS) in regulating biogenesis of RNA-containing EVs (Barman et al., 2022). We identified the ER MCS tether protein VAP-A and the ceramide transporter CERT as key drivers of this process. VAP-A depletion and overexpression produced corresponding changes in the overall number and RNA content of secreted EVs. Further sub-fractionation of small EVs from VAP-A depleted cells revealed a distinct loss in a specific subset of dense, RNA-loaded small EVs that are critical for the transfer of miR-100 to recipient cells. Cell imaging data confirmed the loss of RNA and RNA binding proteins (RBPs) in VAP-A-knockdown multivesicular bodies. Lipid analysis of VAP-A-knockdown EVs revealed decreases in ceramides, which are known to affect EV biogenesis. Depletion of the ceramide transfer protein CERT, which interacts with its binding partner VAP-A at ER MCS, leads to similar defects in EV number and RNA content as VAP-A-knockdown. These data suggest a model for ER MCS as platforms for biogenesis of a key EV population via ceramide transfer and RNA loading.

Keywords: CERT; Endoplasmic reticulum; RNA; VAP-A; ceramide; exosomes; extracellular vesicles

DOI: https://doi.org/10.1177/25152564221121444

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

mSphere. 2023 Apr 05. e0010423

Host Lipid Transport Protein ORP1 Is Necessary for Coxiella burnetii Growth and Vacuole Expansion in Macrophages.

Baleigh Schuler, Margaret Sladek, Stacey D Gilk.

Coxiella burnetii is an intracellular bacterium that causes the human disease Q fever. C. burnetii forms a large, acidic Coxiella-containing vacuole (CCV) and uses a type 4B secretion system to secrete effector proteins into the host cell cytoplasm. While the CCV membrane is rich in sterols, cholesterol accumulation in the CCV is bacteriolytic, suggesting that C. burnetii regulation of lipid transport and metabolism is critical for successful infection. The mammalian lipid transport protein ORP1L (oxysterol binding protein-like protein 1 Long) localizes to the CCV membrane and mediates CCV-endoplasmic reticulum (ER) membrane contact sites. ORP1L functions in lipid sensing and transport, including cholesterol efflux from late endosomes and lysosomes (LELs), and the ER. Its sister isoform, ORP1S (oxysterol binding protein-like protein 1 Short) also binds cholesterol but has cytoplasmic and nuclear localization. In ORP1-null cells, we found that CCVs were smaller than in wild-type cells, highlighting the importance of ORP1 in CCV development. This effect was consistent between HeLa cells and murine alveolar macrophages (MH-S cells). CCVs in ORP1-null cells had higher cholesterol content than CCVs in wild-type cells at 4 days of infection, suggesting ORP1 functions in cholesterol efflux from the CCV. While the absence of ORP1 led to a C. burnetii growth defect in MH-S cells, there was no growth defect in HeLa cells. Together, our data demonstrated that C. burnetii uses the host sterol transport protein ORP1 to promote CCV development, potentially by using ORP1 to facilitate cholesterol efflux from the CCV to diminish the bacteriolytic effects of cholesterol. IMPORTANCE Coxiella burnetii is an emerging zoonotic pathogen and bioterrorism threat. No licensed vaccine exists in the United States, and the chronic form of the disease is difficult to treat and potentially lethal. Postinfectious sequelae of C. burnetii infection, including debilitating fatigue, place a significant burden on individuals and communities recovering from an outbreak. C. burnetii must manipulate host cell processes in order to promote infection. Our results establish a link between host cell lipid transport processes and C. burnetii's avoidance of cholesterol toxicity during infection of alveolar macrophages. Elucidating the mechanisms behind bacterial manipulation of the host will yield insight for new strategies to combat this intracellular pathogen.

Keywords: Coxiella; ORP; cholesterol; intracellular pathogen; membrane contact sites

DOI: https://doi.org/10.1128/msphere.00104-23