bims-mecosi 2023-01-29 papers

Issue of 2023‒01‒29
seven papers selected by
Verena Kohler

J Cell Biol. 2023 Apr 03. pii: e202205133. [Epub ahead of print]222(4):

Tex2 is required for lysosomal functions at TMEM55-dependent ER membrane contact sites.

Yuanjiao Du, Weiping Chang, Lei Gao, Lin Deng, Wei-Ke Ji.

ER tubules form and maintain membrane contact sites (MCSs) with late endosomes/lysosomes (LE/lys). The molecular composition and cellular functions of these MCSs are poorly understood. Here, we find that Tex2, an SMP domain-containing lipid transfer protein conserved in metazoan and yeast, is a tubular ER protein and is recruited to ER-LE/lys MCSs by TMEM55, phosphatases that convert PI(4,5)P2 to PI5P on LE/lys. We show that the Tex2-TMEM55 interaction occurs between an N-terminal region of Tex2 and a catalytic motif in the PTase domain of TMEM55. The Tex2-TMEM55 interaction can be regulated by endosome-resident type 2 PI4K activities. Functionally, Tex2 knockout results in defects in lysosomal trafficking, digestive capacity, and lipid composition of LE/lys membranes. Together, our data identify Tex2 as a tubular ER protein that resides at TMEM55-dependent ER-LE/lys MCSs required for lysosomal functions.

DOI: https://doi.org/10.1083/jcb.202205133

Dev Cell. 2023 Jan 23. pii: S1534-5807(22)00876-0. [Epub ahead of print]58(2): 121-138.e9

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites.

Mélody Subra, Manuela Dezi, Joëlle Bigay, Sandra Lacas-Gervais, Aurélie Di Cicco, Ana Rita Dias Araújo, Sophie Abélanet, Lucile Fleuriot, Delphine Debayle, Romain Gautier, Amanda Patel, Fanny Roussi, Bruno Antonny, Daniel Lévy, Bruno Mesmin.

Membrane contact sites (MCSs) are heterogeneous in shape, composition, and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs that involve the endoplasmic reticulum (ER). Although the VAP-FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs. We report that VAP-A localization to different MCSs depends on its intrinsically disordered regions (IDRs) in human cells. VAP-A interaction with PTPIP51 and VPS13A at ER-mitochondria MCS conditions mitochondria fusion by promoting lipid transfer and cardiolipin buildup. VAP-A also enables lipid exchange at ER-Golgi MCS by interacting with oxysterol-binding protein (OSBP) and CERT. However, removing IDRs from VAP-A restricts its distribution and function to ER-mitochondria MCS. Our data suggest that IDRs do not modulate VAP-A preference toward specific partners but do adjust their geometry to MCS organization and lifetime constraints. Thus, IDR-mediated VAP-A conformational flexibility ensures membrane tethering plasticity and efficiency.

Keywords: Golgi apparatus; VAP; cryo-EM; endoplasmic reticulum; intrinsically disordered region; lipid transfer protein; membrane contact site; membrane tethering; mitochondrial fusion; protein flexibility

DOI: https://doi.org/10.1016/j.devcel.2022.12.010

Acta Histochem. 2023 Jan 23. pii: S0065-1281(23)00006-5. [Epub ahead of print]125(2): 152000

Mitochondria-associated endoplasmic reticulum membranes: A promising toxicity regulation target.

Zehui Hu, Shengyuan Shi, Yiquan Ou, Fangyan Hu, Dingxin Long.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic suborganelle membranes that physically couple endoplasmic reticulum (ER) and mitochondria to provide a platform for exchange of intracellular molecules and crosstalk between the two organelles. Dysfunctions of mitochondria and ER and imbalance of intracellular homeostasis have been discovered in the research of toxics. Cellular activities such as oxidative stress, ER stress, Ca2+ transport, autophagy, mitochondrial fusion and fission, and apoptosis mediated by MAMs are closely related to the toxicological effects of various toxicants. These cellular activities mediated by MAMs crosstalk with each other. Regulating the structure and function of MAMs can alleviate the damage caused by toxicants to some extent. In this review, we discuss the relationships between MAMs and the mechanisms of toxicological effects, and highlight MAMs as a potential target for protection against toxicants.

Keywords: Apoptosis; Ca(2+) homeostasis imbalance; Mitochondria-associated endoplasmic reticulum membranes; Stress response; Toxicology

DOI: https://doi.org/10.1016/j.acthis.2023.152000

Plant Physiol. 2023 Jan 24. pii: kiad035. [Epub ahead of print]

Defining the lipidome of Arabidopsis leaf mitochondria: Specific lipid complement and biosynthesis capacity.

Yi-Tse Liu, Jennifer Senkler, Cornelia Herrfurth, Hans-Peter Braun, Ivo Feussner.

Mitochondria are often considered the power stations of the cell, playing critical roles in various biological processes such as cellular respiration, photosynthesis, stress responses and programmed cell death. To maintain the structural and functional integrities of mitochondria, it is crucial to achieve a defined membrane lipid composition between different lipid classes wherein specific proportions of individual lipid species are present. Although mitochondria are capable of self-synthesizing a few lipid classes, many phospholipids are synthesized in the endoplasmic reticulum and transferred to mitochondria via membrane contact sites, as mitochondria are excluded from the vesicular transportation pathway. However, knowledge on the capability of lipid biosynthesis in mitochondria and the precise mechanism of maintaining the homeostasis of mitochondrial lipids is still scarce. Here we describe the lipidome of mitochondria isolated from Arabidopsis (Arabidopsis thaliana) leaves, including the molecular species of glycerolipids, sphingolipids and sterols, to depict the lipid landscape of mitochondrial membranes. In addition, we define proteins involved in lipid metabolism by proteomic analysis and compare our data with mitochondria from cell cultures since they still serve as model systems. Proteins putatively localized to the membrane contact sites are proposed based on the proteomic results and online databases. Collectively, our results suggest that leaf mitochondria are capable - with the assistance of membrane contact site-localized proteins - of generating several lipid classes including phosphatidylethanolamines, cardiolipins, diacylgalactosylglycerols and free sterols. We anticipate our work to be a foundation to further investigate the functional roles of lipids and their involvement in biochemical reactions in plant mitochondria.

Keywords: Arabidopsis thaliana ; lipidome; mitochondrium; proteome; respiration

DOI: https://doi.org/10.1093/plphys/kiad035

Sci Total Environ. 2023 Jan 21. pii: S0048-9697(23)00356-X. [Epub ahead of print]869 161741

The key role of proteostasis at mitochondria-associated endoplasmic reticulum membrane in vanadium-induced nephrotoxicity using a proteomic strategy.

Xiaoyu Wang, Chenghong Xing, Guyue Li, Xueyan Dai, Xiaona Gao, Yu Zhuang, Huabin Cao, Guoliang Hu, Xiaoquan Guo, Fan Yang.

Excessive vanadium (V) contamination is an attracting growing concern, which can negatively affect the health of human and ecosystems. But how V causes nephrotoxicity and the role of mitochondria-associated endoplasmic reticulum membrane (MAM) in V-induced nephrotoxicity have remained elusive. To explore the detailed mechanism and screen of potential effective drugs for V-evoked nephrotoxicity, a total of 72 ducks were divided into two groups, control group and V group (30 mg/kg V). Results showed that excessive V damaged kidney function of ducks including causing histopathological abnormality, biochemical makers derangement and oxidative stress. Then MAM of duck kidneys was extracted to investigate differentially expressed proteins (DEPs) under V exposure using proteomics analysis. Around 4240 MAM-localized proteins were identified, of which 412 DEPs showed dramatic changes, including 335 upregulated and 77 downregulated DEPs. On the basis of gene ontology (GO), string and KEGG database analysis, excessive V led to nephrotoxicity primarily by affecting MAM-mediated metabolic pathways, especially elevating the endoplasmic Reticulum (ER) proteostasis related pathway. Further validation analysis of the detected genes and proteins of ER proteostasis related pathway under V poisoning revealed a consistent relationship with proteome analysis, indicating that V disrupted MAM-mediated ER proteostasis. Accordingly, our data proved the critical role for MAM in V-evoked nephrotoxicity, particularly with MAM-mediated ER proteostasis, providing promising insights into the toxicological exploration mechanisms of V.

Keywords: ER proteostasis; Kidney; MAM; TMT-based proteomics; Vanadium

DOI: https://doi.org/10.1016/j.scitotenv.2023.161741

Neurobiol Dis. 2023 Jan 20. pii: S0969-9961(23)00023-2. [Epub ahead of print]177 106009

Ethanol-induced ceramide production causes neuronal apoptosis by increasing MCL-1S-mediated ER-mitochondria contacts.

Jae Ryong Lim, Chang Woo Chae, Ji Yong Park, Young Hyun Jung, Jee Hyeon Yoon, Min Jeong Kim, Hyun Jik Lee, Gee Euhn Choi, Ho Jae Han.

Heavy alcohol consumption causes neuronal cell death and cognitive impairment. Neuronal cell death induced by ethanol may result from increased production of the sphingolipid metabolite ceramide. However, the molecular mechanisms of neuronal cell death caused by ethanol-induced ceramide production have not been elucidated. Therefore, we investigated the mechanism through which ethanol-induced ceramide production causes neuronal cell apoptosis using human induced-pluripotent stem cell-derived neurons and SH-SY5Y cells and identified the effects of ceramide on memory deficits in C57BL/6 mice. First, we found that ethanol-induced ceramide production was decreased by inhibition of the de novo synthesis pathway, mediated by serine palmitoyltransferase (SPT). The associated alterations of the molecules related to the ceramide pathway suggest that the elevated level of ceramide activated protein phosphatase 1 (PP1), which inhibited the nuclear translocation of serine/arginine-rich splicing factor 1 (SRSF1). This led to aberrant splicing of myeloid cell leukemia 1 (MCL-1) pre-mRNA, which upregulated MCL-1S expression. Our results demonstrated that the interaction of MCL-1S with the inositol 1, 4, 5-trisphosphate receptor (IP3R) increases calcium release from the endoplasmic reticulum (ER) and then activated ER-bound inverted formin 2 (INF2). In addition, we discovered that F-actin polymerization through INF2 activation promoted ER-mitochondria contacts, which induced mitochondrial calcium influx and mitochondrial reactive oxygen species (mtROS) production. Markedly, MCL-1S silencing decreased mitochondria-associated ER membrane (MAM) formation and prevented mitochondrial calcium influx and mtROS accumulation, by inhibiting INF2-dependent actin polymerization interacting with mitochondria. Furthermore, the inhibition of ceramide production in ethanol-fed mice reduced MCL-1S expression, neuronal cell death, and cognitive impairment. In conclusion, we suggest that ethanol-induced ceramide production may lead to mitochondrial calcium overload through MCL-1S-mediated INF2 activation-dependent MAM formation, which promotes neuronal apoptosis.

Keywords: Ceramide; Cognitive impairment; Ethanol; INF2; MCL-1S; Mitochondria-associated ER membrane (MAM); Neuronal apoptosis

DOI: https://doi.org/10.1016/j.nbd.2023.106009

Front Cell Dev Biol. 2022 ;10 1118314

Editorial: The proceedings of mitochondria apoptosis and cancer (MAC 2021) virtual symposium.

Shazib Pervaiz.

Keywords: MCS; MOMP; cancer; mitochondria; sirt3

DOI: https://doi.org/10.3389/fcell.2022.1118314