bims-mecosi 2022-11-27 papers

Issue of 2022–11–27
six papers selected by
Verena Kohler, University of Graz

Front Cell Dev Biol. 2022 ;10 1076670

Editorial: "Molecular mechanisms and physiological significance of organelle interactions and cooperation-Volume II".

Joseph Costello, Markus Islinger, Michael Schrader.

Keywords: lipid droplets; membrane contact sites; mitochondria; organelle interaction; organelles; peroxisomes

DOI: https://doi.org/10.3389/fcell.2022.1076670

Autophagy. 2022 Nov 24.

TraB, a Novel Plant ER-Mitochondrial Contact Site Protein Functions as a Mitophagy Receptor in Plants.

Patrick Duckney, Chengyang Li, Patrick J Hussey, Pengwei Wang.

Autophagic degradation of mitochondria (known as mitophagy) is known to occur in all eukaryotes, and is important for the turnover of damaged mitochondria and recycling of nutrients during starvation. Targeting of mitochondria for autophagic degradation is regulated by recognition of mitochondrial-localized mitophagy receptors by the autophagy adaptor protein, ATG8, which regulates the formation of phagophore membranes to encapsulate mitochondrial cargo. Mitophagy receptor proteins have been well characterized in animals and yeast; however, proteins that function as mitophagy receptors in plants have not been discovered until now. We have recently characterized the plant TraB-family proteins AT1G05270/TRB1 and AT2G32340/TRB2, as novel mitophagy receptors, elucidating novel mechanisms of mitophagy in plants.

Keywords: Arabidopsis; ER-mitochondrial contact sites; TraB-family proteins; VAP27; mitophagy; mitophagy receptor

DOI: https://doi.org/10.1080/15548627.2022.2151190

CNS Neurosci Ther. 2022 Nov 23.

Disruption of Mitochondrial-associated ER membranes by HIV-1 tat protein contributes to premature brain aging.

Sterling P Arjona, Charles N S Allen, Maryline Santerre, Scott Gross, Jonathan Soboloff, Rosemarie Booze, Bassel E Sawaya.

INTRODUCTION: Mitochondrial-associated ER membranes (MAMs) control many cellular functions, including calcium and lipid exchange, intracellular trafficking, and mitochondrial biogenesis. The disruption of these functions contributes to neurocognitive disorders, such as spatial memory impairment and premature brain aging. Using neuronal cells, we demonstrated that HIV-1 Tat protein deregulates the mitochondria.
METHODS& RESULTS: To determine the mechanisms, we used a neuronal cell line and showed that Tat-induced changes in expression and interactions of both MAM-associated proteins and MAM tethering proteins. The addition of HIV-1 Tat protein alters expression levels of PTPIP51 and VAPB proteins in the MAM fraction but not the whole cell. Phosphorylation of PTPIP51 protein regulates its subcellular localization and function. We demonstrated that the Tat protein promotes PTPIP51 phosphorylation on tyrosine residues and prevents its binding to VAPB. Treatment of the cells with a kinase inhibitor restores the PTPIP51-VAPB interaction and overcomes the effect of Tat.
CONCLUSION: These results suggest that Tat disrupts the MAM, through the induction of PTPIP51 phosphorylation, leading to ROS accumulation, mitochondrial stress, and altered movement. Hence, we concluded that interfering in the MAM-associated cellular pathways contributes to spatial memory impairment and premature brain aging often observed in HIV-1-infected patients.

Keywords: HIV-1-tat; MAM-tethering; PTPIP51; VAPB; aging; memory impairment; mitochondria-associated ER membranes

DOI: https://doi.org/10.1111/cns.14011

Cell Struct Funct. 2022 Nov 22.

Quantitative 3D correlative light and electron microscopy of organelle association during autophagy.

Satoru Takahashi, Chieko Saito, Ikuko Koyama-Honda, Noboru Mizushima.

In macroautophagy, disk-shaped double-membrane structures called phagophores elongate to form cup-shaped structures, becoming autophagosomes upon closure. These autophagosomes then fuse with lysosomes to become autolysosomes and degrade engulfed material. Autophagosome formation is reported to involve other organelles, including the endoplasmic reticulum (ER) and mitochondria. Organelles are also taken up by autophagosomes as autophagy cargos. However, few studies have performed systematic spatiotemporal analysis of inter-organelle relationships during macroautophagy. Here, we investigated the organelles in contact with phagophores, autophagosomes, and autolysosomes by using three-dimensional correlative light and electron microscopy with array tomography in cells starved 30 min. As previously reported, all phagophores associate with the ER. The surface area of phagophores in contact with the ER decreases gradually as they mature into autophagosomes and autolysosomes. However, the ER still associates with 92% of autophagosomes and 79% of autolysosomes, suggesting that most autophagosomes remain on the ER after closure and even when they fuse with lysosomes. In addition, we found that phagophores form frequently near other autophagic structures, suggesting the presence of potential hot spots for autophagosome formation. We also analyzed the contents of phagophores and autophagosomes and found that the ER is the most frequently engulfed organelle (detected in 65% of total phagophores and autophagosomes). These quantitative three-dimensional ultrastructural data provide insights into autophagosome-organelle relationships during macroautophagy. Key words: 3D-CLEM, autophagosome, electron microscopy, endoplasmic reticulum, lysosome.

Keywords: 3D-CLEM; autophagosome; electron microscopy; endoplasmic reticulum; lysosome

DOI: https://doi.org/10.1247/csf.22071

EMBO J. 2022 Nov 21. e112677

Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair.

Maja Radulovic, Eva Maria Wenzel, Sania Gilani, Lya Kk Holland, Alf Håkon Lystad, Santosh Phuyal, Vesa M Olkkonen, Andreas Brech, Marja Jäättelä, Kenji Maeda, Camilla Raiborg, Harald Stenmark.

Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP-ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol-PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.

Keywords: cholesterol; lysosome; membrane contact site; membrane repair; phosphoinositide

DOI: https://doi.org/10.15252/embj.2022112677

Front Cell Dev Biol. 2022 ;10 995732

Liver mitochondria-associated endoplasmic reticulum membrane proteomics for studying the effects of ZiBuPiYin recipe on Zucker diabetic fatty rats after chronic psychological stress.

Huiying Xu, Wen Zhou, Libin Zhan, Tingting Bi, Xiaoguang Lu.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease with multiple etiologies, involving both genetic and environmental factors. With changes associated with modern life, increasing attention has been paid to chronic psychological stressors such as work stress. Chronic psychological stress can induce or aggravate diabetes mellitus, and conversely, with the deterioration of T2DM, patients often experience different degrees of depression, anxiety, and other negative emotions. In order to clarify the role of ZiBuPiYin recipe (ZBPYR) in regulating the liver mitochondria-associated endoplasmic reticulum membrane proteome to improve T2DM with chronic psychological stress, differentially expressed proteins (DEPs) were identified among Zucker lean littermates (control group), chronic psychological stress T2DM rats (model group), and ZBPYR administration rats (ZBPYR group) through iTRAQ with LC-MS/MS. Using Mfuzz soft clustering analysis, DEPs were divided into six different clusters. Clusters 1-6 contained 5, 68, 44, 57, 28, and 32 DEPs, respectively. Given that ZBPYR can alleviate T2DM symptoms and affect exploratory behavior during T2DM with chronic psychological stress, we focused on the clusters with opposite expression trends between model:control and ZBPYR:model groups. We screened out the DEPs in clusters 1, 3, and 4, which may be good candidates for the prevention and treatment of T2DM with chronic psychological stress, and further conducted bioinformatics analyses. DEPs were mainly involved in the insulin signaling pathway, oxidative phosphorylation, tricarboxylic acid cycle, amino acid metabolism, lysosome-related processes, and lipid metabolism. This may indicate the pathogenic basis of T2DM with chronic psychological stress and the potential therapeutic mechanism of ZBPYR. In addition, two key proteins, lysosome-associated protein (Lamp2) and tricarboxylic acid cycle-related protein (Suclg1), may represent novel biomarkers for T2DM with chronic psychological stress and drug targets of ZBPYR. Western blot analyses also showed similar expression patterns of these two proteins in liver MAMs of the model and ZBPYR groups.

Keywords: ZiBuPiYin recipe; chronic psychological stress; mitochondria-associated ER membrane; proteomics; type 2 diabetes mellitus

DOI: https://doi.org/10.3389/fcell.2022.995732