bims-mecosi 2023-12-17 papers

Issue of 2023–12–17
seven papers selected by
Verena Kohler, Umeå University

bioRxiv. 2023 Nov 29. pii: 2023.11.29.569289. [Epub ahead of print]

A fluorogenic complementation tool kit for interrogating lipid droplet-organelle interaction.

Xiao Li, Rico Gamuyao, Ming-Lun Wu, Woo Jung Cho, Nathan B Kurtz, Sharon V King, R A Petersen, Daniel R Stabley, Caleb Lindow, Leslie Climer, Abbas Shirinifard, Francesca Ferrara, Robert E Throm, Camenzind G Robinson, Alex Carisey, Alison G Tebo, Chi-Lun Chang.

Contact sites between lipid droplets and other organelles are essential for cellular lipid and energy homeostasis. Detection of these contact sites at nanometer scale over time in living cells is challenging. Here, we developed a tool kit for detecting contact sites based on F luorogen- A ctivated B imolecular complementation at CON tact sites, FABCON, using a reversible, low affinity split fluorescent protein, splitFAST. FABCON labels contact sites with minimal perturbation to organelle interaction. Via FABCON, we quantitatively demonstrated that endoplasmic reticulum (ER)- and mitochondria (mito)-lipid droplet contact sites are dynamic foci in distinct metabolic conditions, such as during lipid droplet biogenesis and consumption. An automated analysis pipeline further classified individual contact sites into distinct subgroups based on size, likely reflecting differential regulation and function. Moreover, FABCON is generalizable to visualize a repertoire of organelle contact sites including ER-mito. Altogether, FABCON reveals insights into the dynamic regulation of lipid droplet-organelle contact sites and generates new hypotheses for further mechanistical interrogation during metabolic switch.

DOI: https://doi.org/10.1101/2023.11.29.569289

Front Cell Dev Biol. 2023 ;11 1291506

The role of extended synaptotagmin at membrane contact sites in cancer research.

Yuetian Pan, Dorothee Strohmer, Shikai Feng, Guibin Zhang, Hongshang Cui, Yongbin Song.

Membrane contact sites (MCSs) are adjacent locations between the membranes of two different organelles and play important roles in various physiological processes, including cellular calcium and lipid signaling. In cancer research, MCSs have been proposed to regulate tumor metabolism and fate, contributing to tumor progression, and this function could be exploited for tumor therapy. However, there is little evidence on how MCSs are involved in cancer progression. In this review, we use extended synaptotagmins (E-Syts) as an entry point to describe how MCSs affect cancer progression and may be used as new diagnostic biomarkers. We then introduced the role of E-Syt and its related pathways in calcium and lipid signaling, aiming to explain how MCSs affect tumor proliferation, progression, metastasis, apoptosis, drug resistance, and treatment through calcium and lipid signaling. Generally, this review will facilitate the understanding of the complex contact biology of cancer cells.

Keywords: calcium signaling; cancer progression; lipid signaling; membrane contact sites; metastasis

DOI: https://doi.org/10.3389/fcell.2023.1291506

Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231195718

A Possible Role of VPS13B in the Formation of Golgi-Lipid Droplet Contacts Associating with the ER.

Yuanjiao Du, Xuewen Hu, Weiping Chang, Lin Deng, Wei-Ke Ji, Juan Xiong.

While the physical interactions between the Golgi apparatus (Golgi) and lipid droplets (LDs) have been suggested through system-level imaging, the Golgi-LD membrane contact sites (MCSs) remain largely uncharacterized. Here, we show evidence to support the existence of Golgi-LD MCSs in HEK293 cells. We further suggest that vacuolar protein sorting-associated protein 13B (VPS13B) localizes to and promotes the formation of Golgi-LD contacts upon oleic acid (OA) stimulation using 3D high-resolution microscopy. Depletion of VPS13B moderately affects the formation of Golgi-LD contacts upon OA treatment in addition to the fragmentation of the Golgi. Although cellular functions of VPS13B-mediated contacts are still elusive, these findings may provide a new insight into related diseases caused by loss-of-function mutations of VPS13B.

Keywords: Golgi; VPS13B; endoplasmic reticulum; lipid droplet; membrane contact sites

DOI: https://doi.org/10.1177/25152564231195718

Cell Rep. 2023 Dec 05. pii: S2211-1247(23)01552-8. [Epub ahead of print]42(12): 113540

The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation.

Amado Carreras-Sureda, Xin Zhang, Loann Laubry, Jessica Brunetti, Stéphane Koenig, Xiaoxia Wang, Cyril Castelbou, Claudio Hetz, Yong Liu, Maud Frieden, Nicolas Demaurex.

Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule (STIM)-gated ORAI channels at endoplasmic reticulum (ER) and plasma membrane (PM) contact sites maintains adequate levels of Ca2+ within the ER lumen during Ca2+ signaling. Disruption of ER Ca2+ homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Here, we report that the UPR transducer inositol-requiring enzyme 1 (IRE1) interacts with STIM1, promotes ER-PM contact sites, and enhances SOCE. IRE1 deficiency reduces T cell activation and human myoblast differentiation. In turn, STIM1 deficiency reduces IRE1 signaling after store depletion. Using a CaMPARI2-based Ca2+ genome-wide screen, we identify CAMKG2 and slc105a as SOCE enhancers during ER stress. Our findings unveil a direct crosstalk between SOCE and UPR via IRE1, acting as key regulator of ER Ca2+ and proteostasis in T cells and muscles. Under ER stress, this IRE1-STIM1 axis boosts SOCE to preserve immune cell functions, a pathway that could be targeted for cancer immunotherapy.

Keywords: CP: Cell biology; CP: Immunology; CRISPR screening; CaMPARI; ER stress; IRE1; SOCE; STIM1; T cells; calcium; muscle

DOI: https://doi.org/10.1016/j.celrep.2023.113540

Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938

The critical roles of STING in mitochondrial homeostasis.

Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.

The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.

Keywords: Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING

DOI: https://doi.org/10.1016/j.bcp.2023.115938

Prog Retin Eye Res. 2023 Dec 11. pii: S1350-9462(23)00070-8. [Epub ahead of print] 101231

The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.

Sarah X Zhang, Josh J Wang, Christopher R Starr, Eun-Jin Lee, Sophia Park, Assylbek Zhylkibayev, Andy Medina, Jonathan H Lin, Marina Gorbatyuk.

The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.

Keywords: Autophagy; Diabetic retinopathy; Endoplasmic reticulum; Integrated stress response; Mitochondria; Protein homeostasis; Retina; Retinal degeneration; Unfolded protein response

DOI: https://doi.org/10.1016/j.preteyeres.2023.101231

J Hazard Mater. 2023 Nov 30. pii: S0304-3894(23)02426-3. [Epub ahead of print]465 133142

Nanoplastic propels diet-induced NAFL to NASH via ER-mitochondrial tether-controlled redox switch.

Jie Wei, Jintao Liu, Huan Wang, Kai Wen, Xiuye Ni, Yilong Lin, Jingru Huang, Xiang You, Zhao Lei, Juan Li, Heqing Shen, Yi Lin.

Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH.

Keywords: Environmental metabolism disruptor/ Ip3r1/ Non‐alcoholic fatty liver disease / Vdac1 /Nrf2

DOI: https://doi.org/10.1016/j.jhazmat.2023.133142