bims-mecosi 2023-02-05 papers

Issue of 2023–02–05
nine papers selected by
Verena Kohler, University of Graz

Cell Calcium. 2023 Jan 25. pii: S0143-4160(23)00012-X. [Epub ahead of print]110 102700

IP3 receptor trafficking at the ER-mitochondria contacts impacts on mitochondrial Ca2+ homeostasis and metabolism.

Karim Rahhali, Fabio Di Lisa, Nina Kaludercic.

The close contacts between endoplasmic reticulum and mitochondria (ERMCs) play a key role in metabolic regulation, Ca2+ homeostasis, reactive oxygen species production, and many other cell functions. Nevertheless, it is not fully clear how these contacts dynamically rearrange to support cell functions. In a recent Nature Communications article [1], Katona et al. elegantly showed that motile IP3Rs can be captured at ERMCs to promptly mediate Ca2+ transfer and stimulate mitochondrial oxidative metabolism.

Keywords: Contact sites; Endoplasmic reticulum; IP(3) receptor; Mitochondria

DOI: https://doi.org/10.1016/j.ceca.2023.102700

Curr Opin Chem Biol. 2023 Jan 31. pii: S1367-5931(22)00147-8. [Epub ahead of print]73 102262

Chemo- and opto-genetic tools for dissecting the role of membrane contact sites in living cells: Recent advances and limitations.

Fubito Nakatsu, Shinya Tsukiji.

Membrane contact sites (MCSs) are morphologically defined intracellular structures where cellular membranes are closely apposed. Recent progress has significantly advanced our understanding of MCSs with the use of new tools and techniques. Visualization of MCSs in living cells by split fluorescence proteins or FRET-based techniques tells us the dynamic property of MCSs. Manipulation of MCSs by chemically-induced dimerization (CID) or light-induced dimerization (LID) greatly contributes to our understanding of their functional aspects including inter-organelle lipid transport mediated by lipid transfer proteins (LTPs). Here we highlight recent advances in these tools and techniques as applied to MCSs, and we discuss their advantages and limitations.

Keywords: Chemically-induced dimerization; Fluorescent probes; Imaging; Light-induced dimerization; Lipid transfer protein; Membrane contact site; Phosphoinositides

DOI: https://doi.org/10.1016/j.cbpa.2022.102262

Neurobiol Dis. 2023 Feb 01. pii: S0969-9961(23)00045-1. [Epub ahead of print] 106031

Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis.

Seiji Watanabe, Mai Horiuchi, Yuri Murata, Okiru Komine, Noe Kawade, Akira Sobue, Koji Yamanaka.

Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Alternations of the mitochondria-associated membranes (MAM), one of the organelle contact sites where the endoplasmic reticulum (ER) is tethered to the mitochondria, have been involved in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the detailed mechanisms through which MAM integrity is disrupted in ALS have not been fully elucidated. Here, we examined whether AAA ATPase domain-containing protein 3A (ATAD3A), a mitochondrial membrane AAA ATPase accumulating at the MAM, is involved in ALS. We found that sigma-1 receptor (σ1R), an ER-resident MAM protein causative for inherited juvenile ALS, required ATAD3A to maintain the MAM. In addition, σ1R retained ATAD3A as a monomer, which is associated with an inhibition of mitochondrial fragmentation. ATAD3A dimerization and mitochondrial fragmentation were significantly induced in σ1R-deficient or SOD1-linked ALS mouse spinal cords. Overall, these observations indicate that MAM induction by σ1R depends on ATAD3A and that σ1R maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation. Our findings suggest that targeting σ1R-ATAD3A axis would be promising for a novel therapeutic strategy to treat mitochondrial dysfunction in neurological disorders, including ALS.

Keywords: ATPase domain-containing; Lateral sclerosis; Mitochondria-associated membrane/sigma-1; Protein 3A/amyotrophic; Receptor/AAA

DOI: https://doi.org/10.1016/j.nbd.2023.106031

Autophagy. 2023 Feb 02.

A distinct linker mediating ER-autophagosome membrane contact site (EACS) in plants.

Hao Ye, Jiayang Gao, Liwen Jiang.

Endoplasmic reticulum (ER) membrane contacts play a central role in regulating autophagosome formation in yeast and mammals. However, a direct functional linkage between the ER and autophagosomes in plants remains elusive. We have recently identified and characterized a plant-unique protein complex consisting of AT4G22540/OSBP2A/ORP2A (oxysterol binding protein-related protein 2A), the ER resident protein AT3G60600/VAP27-1 (vesicle-associated protein 27-1) and AT2G45170/ATG8e (autophagy related 8e) that mediate the ER-autophagosome membrane contact site (EACS) in the model plant Arabidopsis thaliana. Knockdown (KD) of ORP2A affects autophagosome formation and seedling development, whereas ORP2A KD root cells show accumulation of the macroautophagic/autophagic core machinery and PtdIns3P in enlarged ER membranes under autophagy conditions. This study reveals the molecular architecture and functions of a distinct plant EACS in regulating autophagosome formation via lipid redistribution.

Keywords: Arabidopsis; ORP; PtdIns3P; autophagosome; membrane contact site

DOI: https://doi.org/10.1080/15548627.2023.2176028

JHEP Rep. 2023 Mar;5(3): 100647

Hepatitis C virus replication requires integrity of mitochondria-associated ER membranes.

Sarah Duponchel, Lea Monnier, Jennifer Molle, Nadia Bendridi, Muhammad Rizwan Alam, Ahmed Gaballah, Boyan Grigorov, Alexander Ivanov, Marcel Schmiel, Margarete Odenthal, Michel Ovize, Jennifer Rieusset, Fabien Zoulim, Birke Bartosch.

Background & Aims: Chronic HCV infection causes cellular stress, fibrosis and predisposes to hepatocarcinogenesis. Mitochondria play key roles in orchestrating stress responses by regulating bioenergetics, inflammation and apoptosis. To better understand the role of mitochondria in the viral life cycle and disease progression of chronic hepatitis C, we studied morphological and functional mitochondrial alterations induced by HCV using productively infected hepatoma cells and patient livers.
Methods: Biochemical and imaging assays were used to assess localization of cellular and viral proteins and mitochondrial functions in cell cultures and liver biopsies. Cyclophilin D (CypD) knockout was performed using CRISPR/Cas9 technology. Viral replication was quantified by quantitative reverse-transcription PCR and western blotting.
Results: Several HCV proteins were found to associate with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), the points of contact between the ER and mitochondria. Downregulation of CypD, which is known to disrupt MAM integrity, reduced viral replication, suggesting that MAMs play an important role in the viral life cycle. This process was rescued by ectopic CypD expression. Furthermore, HCV proteins were found to associate with voltage dependent anion channel 1 (VDAC1) at MAMs and to reduce VDAC1 protein levels at MAMs in vitro and in patient biopsies. This association did not affect MAM-associated functions in glucose homeostasis and Ca2+ signaling.
Conclusions: HCV proteins associate specifically with MAMs and MAMs play an important role in viral replication. The association between viral proteins and MAMs did not impact Ca2+ signaling between the ER and mitochondria or glucose homeostasis. Whether additional functions of MAMs and/or VDAC are impacted by HCV and contribute to the associated pathology remains to be assessed.
Impact and implications: Hepatitis C virus infects the liver, where it causes inflammation, cell damage and increases the long-term risk of liver cancer. We show that several HCV proteins interact with mitochondria in liver cells and alter the composition of mitochondrial subdomains. Importantly, HCV requires the architecture of these mitochondrial subdomains to remain intact for efficient viral replication.

Keywords: CypD, cyclophilin D; DMVs, double membrane vesicles; EM, electron microscopy; ER, endoplasmic reticulum; Grp75, glucose-regulated protein 75; HCC, hepatocellular carcinoma; HCVcc, cell culture-derived HCV; IP, immunoprecipitation; IP3R1, inositol trisphosphate receptor 1; KO, knockout; MAMs, mitochondria-associated ER membranes; MOI, multiplicity of infection; OMM, outer mitochondrial membrane; PLA, proximity ligation assay; S1R, sigma 1 receptor; VDAC, voltage-dependent anion channel; dpi, days post infection; fibrosis; hepatitis C virus; mitochondria-associated ER membranes; voltage-dependent anion channel 1

DOI: https://doi.org/10.1016/j.jhepr.2022.100647

Front Immunol. 2022 ;13 1034317

Traffic jam within lymphocytes: A clinician's perspective.

Smitha Hosahalli Vasanna, Jignesh Dalal.

With the discovery of novel diseases and pathways, as well as a new outlook on certain existing diseases, cellular trafficking disorders attract a great deal of interest and focus. Understanding the function of genes and their products in protein and lipid synthesis, cargo sorting, packaging, and delivery has allowed us to appreciate the intricate pathophysiology of these biological processes at the molecular level and the multi-system disease manifestations of these disorders. This article focuses primarily on lymphocyte intracellular trafficking diseases from a clinician's perspective. Familial hemophagocytic lymphohistiocytosis is the prototypical disease of abnormal vesicular transport in the lymphocytes. In this review, we highlight other mechanisms involved in cellular trafficking, including membrane contact sites, autophagy, and abnormalities of cytoskeletal structures affecting the immune cell function, based on a newer classification system, along with management aspects of these conditions.

Keywords: HLH Hemophagocytic lymphohistiocytosis; autophagy; cellular trafficking; hematopoietic stem cell transplantation; immune dysregulation

DOI: https://doi.org/10.3389/fimmu.2022.1034317

Cell Calcium. 2023 Jan 27. pii: S0143-4160(23)00013-1. [Epub ahead of print]110 102701

Regulation and role of calcium in cellular senescence.

Nadine Martin, Kexin Zhu, Joanna Czarnecka-Herok, Mathieu Vernier, David Bernard.

Cellular senescence is a state of stable cell proliferation arrest accompanied by a distinct secretory program impacting the senescent cell microenvironment. This phenotype can be induced by many stresses, including telomere shortening, oncogene activation, oxidative or genotoxic stress. Cellular senescence plays a key role in the organism throughout life, with beneficial effects at a young age for instance in embryonic development and wound healing, and deleterious effects during aging and in aging-related diseases. In the last decade calcium and calcium signaling have been established as critical factors in the implementation and regulation of cellular senescence. In this review we will present and discuss the main discoveries in this field, from the observation of an increased intracellular calcium concentration in senescent cells to the identification of calcium-binding proteins, calcium channels (TRP, ITPR, …) and MERCs (mitochondria-endoplasmic reticulum contact sites) as key players in this context.

Keywords: Aging; Calcium; Cancer; Mitochondria-ER contacts; Senescence; Signaling

DOI: https://doi.org/10.1016/j.ceca.2023.102701

Sci Signal. 2023 Jan 31. 16(770): eabo4457

Deciphering functional roles and interplay between Beclin1 and Beclin2 in autophagosome formation and mitophagy.

Justin M Quiles, Rita H Najor, Eileen Gonzalez, Monica Jeung, Wenjing Liang, Sarah M Burbach, Erika A Zumaya, Rachel Y Diao, Mark A Lampert, Åsa B Gustafsson.

The degradation of macromolecules and organelles by the process of autophagy is critical for cellular homeostasis and is often compromised during aging and disease. Beclin1 and Beclin2 are implicated in autophagy induction, and these homologs share a high degree of amino acid sequence similarity but have divergent N-terminal regions. Here, we investigated the functions of the Beclin homologs in regulating autophagy and mitophagy, a specialized form of autophagy that targets mitochondria. Both Beclin homologs contributed to autophagosome formation, but a mechanism of autophagosome formation independent of either Beclin homolog occurred in response to starvation or mitochondrial damage. Mitophagy was compromised only in Beclin1-deficient HeLa cells and mouse embryonic fibroblasts because of defective autophagosomal engulfment of mitochondria, and the function of Beclin1 in mitophagy required the phosphorylation of the conserved Ser15 residue by the kinase Ulk1. Mitochondria-ER-associated membranes (MAMs) are important sites of autophagosome formation during mitophagy, and Beclin1, but not Beclin2 or a Beclin1 mutant that could not be phosphorylated at Ser15, localized to MAMs during mitophagy. Our findings establish a regulatory role for Beclin1 in selective mitophagy by initiating autophagosome formation adjacent to mitochondria, a function facilitated by Ulk1-mediated phosphorylation of Ser15 in its distinct N-terminal region.

DOI: https://doi.org/10.1126/scisignal.abo4457