bims-mecosi 2023-10-22 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2023‒10‒22
ten papers selected by
Verena Kohler, Umeå University

Contact sites between host organelles and pathogens: boon or bane?
Organelles are miscommunicating: Membrane contact sites getting hijacked by pathogens.
Vitamin E succinate mediated apoptosis by juxtaposing endoplasmic reticulum and mitochondria.
Inhibition of calcium imbalance protects hepatocytes from vanadium exposure-induced inflammation by mediating mitochondrial-associated endoplasmic reticulum membranes in ducks.
StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.
Loss of INPP5K attenuates IP3-induced Ca2+ responses in the glioblastoma cell line U-251 MG cells.
Mechanisms of Nonvesicular Ceramide Transport.
α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.
ARP2/3 complex associates with peroxisomes to participate in pexophagy in plants.
ATAD3 Proteins: Unique Mitochondrial Proteins Essential for Life in Diverse Eukaryotic Lineages.

mSphere. 2023 Oct 18. e0044823

Contact sites between host organelles and pathogens: boon or bane?

Chahat Mehra, Lena Pernas.

  A microbe and its host are in constant communication. An emerging platform for direct communication is the membrane contact sites that form between several pathogens and host organelles. Here, we review our progress on the molecular mechanisms underlying contact sites between host mitochondria and the human parasite Toxoplasma gondii. We discuss open questions regarding their function during infection as well as those formed between the host endoplasmic reticulum and Toxoplasma.

Keywords:  Toxoplasma gondii; endoplasmic reticulum; membrane; membrane contact sites; mitochondria; pathogens

DOI:  https://doi.org/10.1128/msphere.00448-23
Virulence. 2023 Dec;14(1): 2265095

Organelles are miscommunicating: Membrane contact sites getting hijacked by pathogens.

Pratyashaa Paul, Bhavana Tiwari.

  Membrane Contact Sites (MCS) are areas of close apposition of organelles that serve as hotspots for crosstalk and direct transport of lipids, proteins and metabolites. Contact sites play an important role in Ca2+ signalling, phospholipid synthesis, and micro autophagy. Initially, altered regulation of vesicular trafficking was regarded as the key mechanism for intracellular pathogen survival. However, emerging studies indicate that pathogens hijack MCS elements - a novel strategy for survival and replication in an intracellular environment. Several pathogens exploit MCS to establish direct contact between organelles and replication inclusion bodies, which are essential for their survival within the cell. By establishing this direct control, pathogens gain access to cytosolic compounds necessary for replication, maintenance, escaping endocytic maturation and circumventing lysosome fusion. MCS components such as VAP A/B, OSBP, and STIM1 are targeted by pathogens through their effectors and secretion systems. In this review, we delve into the mechanisms which operate in the evasion of the host immune system when intracellular pathogens hostage MCS. We explore targeting MCS components as a novel therapeutic approach, modifying molecular pathways and signalling to address the disease's mechanisms and offer more effective, tailored treatments for affected individuals.

Keywords:  Membrane contact sites (MCS); direct lipid transport; host immune evasion; inter-organellar contacts; non-vesicular trafficking

DOI:  https://doi.org/10.1080/21505594.2023.2265095
Biochim Biophys Acta Gen Subj. 2023 Oct 12. pii: S0304-4165(23)00183-6. [Epub ahead of print]1867(12): 130485

Vitamin E succinate mediated apoptosis by juxtaposing endoplasmic reticulum and mitochondria.

Manobendro Nath Ray, Michiko Kiyofuji, Mizune Ozono, Kentaro Kogure.

  Vitamin E succinate (VES) is an esterified form of natural α-tocopherol, has turned out to be novel anticancer agent. However, its anticancer mechanisms have not been illustrated. Previously, we reported VES mediated Ca2+ release from the endoplasmic reticulum (ER) causes mitochondrial Ca2+ overload, leading to mitochondrial depolarization and apoptosis. Here, we elucidated the mechanism of VES-induced Ca2+ transfer from ER to mitochondria by investigating the role of VES in ER-mitochondria contact formation. Transmission electron microscopic observation confirms VES mediated ER-mitochondria contact while fluorescence microscopic analysis revealed that VES increased mitochondria-associated ER membrane (MAM) formation. Pre-treatment with the inositol 1,4,5-triphosphate receptor (IP3R) antagonist 2-aminoethyl diphenylborinate (2-APB) decreased VES-induced MAM formation, suggesting the involvement of VES-induced Ca2+ efflux from ER in MAM formation. The ER IP3R receptor is known to interact with voltage-dependent anion channels (VDAC) via the chaperone glucose-regulated protein 75 kDa (GRP75) to bring ER and mitochondria nearby. Although we revealed that VES treatment does not affect GRP75 protein level, it increases GRP75 localization in the MAM. In addition, the inhibition of Ca2+ release from ER by 2-APB decreases GRP75 localization in the MAM, suggesting the possibility of Ca2+-induced conformational change of GRP75 that promotes formation of the IP3R-GRP75-VDAC complex and thereby encourages MAM formation. This study identifies the mechanism of VES-induced enhanced Ca2+ transfer from ER to mitochondria, which causes mitochondrial Ca2+ overload leading to apoptosis.

Keywords:  Apoptosis; Ca(2+) transfer; ER-mitochondria contact; GRP75; Vitamin E succinate

DOI:  https://doi.org/10.1016/j.bbagen.2023.130485
Poult Sci. 2023 Aug 18. pii: S0032-5791(23)00532-1. [Epub ahead of print]102(12): 103013

Inhibition of calcium imbalance protects hepatocytes from vanadium exposure-induced inflammation by mediating mitochondrial-associated endoplasmic reticulum membranes in ducks.

Yiling Zhang, Guyue Li, Yanqing Zhao, Xueyan Dai, Mingwen Hu, Huabin Cao, Kai Huang, Fan Yang.

  Vanadium (V) is an essential mineral element in animals, but excessive V can lead to many diseases, affecting the health of humans and animals. However, the molecular crosstalk between mitochondria-associated endoplasmic reticulum membranes (MAMs) and inflammation under V exposure is still at the exploratory stage. This study was conducted to determine the molecular crosstalk between MAMs and inflammation under V exposure in ducks. In this study, duck hepatocytes were treated with NaVO3 (0 μM, 100 μM, and 200 μM) and 2-aminoethyl diphenyl borate (2-APB) (IP3R inhibitor) alone or in combination for 24 h. The data showed that V exposure-induced cell vacuolization, enlarged intercellular space, and decreased density and viability. Meanwhile, hydrogen peroxide (H2O2), malonaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and reactive oxygen species (ROS) levels were upregulated under V treatment. In addition, excessive V could lead to a marked reduction in the MAMs structure, destruction of the membrane structure and overload of intracellular Ca2+ and mitochondrial Ca2+. Moreover, V treatment resulted in notable upregulation of the levels of MAMs-relevant factors (IP3R, Mfn2, Grp75, MCU, VDAC1) but downregulated the levels of IL-18, IL-1β, and lactate dehydrogenase (LDH) in the cell supernatant. Additionally, it also significantly elevated the levels of inflammation-relevant factors (NLRP3, ASC, caspase-1, MAVS, IL-18, IL-1β, and TXNIP). However, the inhibition of IP3R expression attenuated the V-induced variations in the above indicators. Collectively, our results revealed that the maintenance of calcium homeostasis could protect duck hepatocytes from V-induced inflammation injury via MAMs.

Keywords:  calcium homeostasis; hepatocyte; inflammation; mitochondria-associated endoplasmic reticulum membrane; vanadium

DOI:  https://doi.org/10.1016/j.psj.2023.103013
FEBS J. 2023 Oct 16.

StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.

María L Rojas, Juan Pablo Muñoz, Jésica Flores-Martín, Paula Sànchez-Fernàndez-de-Landa, Mariano Cruz Del Puerto, Susana Genti-Raimondi, Antonio Zorzano.

  StarD7 is a member of the START protein family required for phosphatidylcholine delivery to the mitochondria, thus key to maintain mitochondrial structure. Its deficiency has been associated with an impairment of cellular processes, such as proliferation and migration, and it has also been reported that it is needed in myogenic differentiation. Here, we show that StarD7 deficiency in C2C12 muscle cells results in the accumulation of abnormal mitochondria, a reduced number of mitochondria per cell area and increased glycolysis. In addition, StarD7-deficient cells undergo an increase in mitochondria-ER contact sites, reduced connexin 43 expression, and disturbances in lipid handling, evidenced by lipid droplet accumulation and decreased levels in phosphatidylserine synthase 1 and 2 expression. Interestingly, StarD7-deficient cells showed alterations in mitophagy markers. We observed accumulation of LC3B-II and BNIP3 proteins in mitochondria-enriched fractions and accumulation of autophagolysosomal and lysosomal vesicles in StarD7-deficient cells. Furthermore, live-cell imaging experiments of StarD7 knockdown cells expressing mitochondria-targeted mKeima indicated an enhanced mitochondria delivery into lysosomes. Importantly, StarD7 reconstitution in StarD7-deficient cells restores LC3B-II expression in mitochondria-enriched fractions at similar levels to those observed in control cells. Collectively, these findings suggest that StarD7-deficient C2C12 myoblasts are associated with altered cristae structure, disturbances in neutral lipid accumulation, glucose metabolism, and increased mitophagy flux. The alterations mentioned above allow for the maintenance of mitochondrial function.

Keywords:  StarD7; cristae morphology; lipid droplet; mitophagy

DOI:  https://doi.org/10.1111/febs.16979
BBA Adv. 2023 ;4 100105

Loss of INPP5K attenuates IP3-induced Ca2+ responses in the glioblastoma cell line U-251 MG cells.

Jens Loncke, Tomas Luyten, Ana Raquel Ramos, Christophe Erneux, Geert Bultynck.

  INPP5K (inositol polyphosphate 5-phosphatase K) is an endoplasmic reticulum (ER)-resident enzyme that acts as a phosphoinositide (PI) 5-phosphatase, capable of dephosphorylating various PIs including PI 4,5-bisphosphate (PI(4,5)P2), a key phosphoinositide found in the plasma membrane. Given its ER localization and substrate specificity, INPP5K may play a role in ER-plasma membrane contact sites. Furthermore, PI(4,5)P2 serves as a substrate for phospholipase C, an enzyme activated downstream of extracellular agonists acting on Gq-coupled receptors or tyrosine-kinase receptors, leading to IP3 production and subsequent release of Ca2+ from the ER, the primary intracellular Ca2+ storage organelle. In this study, we investigated the impact of INPP5K on ER Ca2+ dynamics using a previously established INPP5K-knockdown U-251 MG glioblastoma cell model. We here describe that loss of INPP5K impairs agonist-induced, IP3 receptor (IP3R)-mediated Ca2+ mobilization in intact cells, while the ER Ca2+ content and store-operated Ca2+ influx remain unaffected. To further elucidate the underlying mechanisms, we examined Ca2+ release in permeabilized cells stimulated with exogenous IP3. Interestingly, the absence of INPP5K also disrupted IP3-induced Ca2+ release events. These results suggest that INPP5K may directly influence IP3R activity through mechanisms yet to be resolved. The findings from this study point towards role of INPP5K in modulating ER calcium dynamics, particularly in relation to IP3-mediated signaling pathways. However, further work is needed to establish the general nature of our findings and to unravel the exact molecular mechanisms underlying the interplay between INNP5K function and Ca2+ signaling.

Keywords:  Calcium signaling; IP3 receptors; Inositol polyphosphate 5-phosphatase K; PI(4,5)P2

DOI:  https://doi.org/10.1016/j.bbadva.2023.100105
Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231208250

Mechanisms of Nonvesicular Ceramide Transport.

Lena Clausmeyer, Florian Fröhlich.

  Ceramides, as key components of cellular membranes, play essential roles in various cellular processes, including apoptosis, cell proliferation, and cell signaling. Ceramides are the precursors of all complex sphingolipids in eukaryotic cells. They are synthesized in the endoplasmic reticulum and are further processed at the Golgi apparatus. Therefore, ceramides have to be transported between these two organelles. In mammalian cells, the ceramide transfer protein forms a contact site between the ER and the trans-Golgi region and transports ceramide utilizing its steroidogenic acute regulatory protein-related lipid transfer domain. In yeast, multiple mechanisms of nonvesicular ceramide transport have been described. This involves the nuclear-vacuolar junction protein Nvj2, the yeast tricalbin proteins, and the lipocalin-like protein Svf1. This review aims to provide a comprehensive overview of nonvesicular ceramide transport mechanisms and their relevance in cellular physiology. We will highlight the physiological and pathological consequences of perturbations in nonvesicular ceramide transport and discuss future challenges in identifying and analyzing ceramide transfer proteins.

Keywords:  Nvj2; Svf1; ceramide; ceramide transport protein; transport; tricalbins

DOI:  https://doi.org/10.1177/25152564231208250
Cell Rep. 2023 Oct 13. pii: S2211-1247(23)01256-1. [Epub ahead of print]42(10): 113244

α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.

Jonathan D Horvath, Maria Casas, Candice Kutchukian, Sara Creus Sánchez, Melissa R Pergande, Stephanie M Cologna, Sergi Simó, Rose E Dixon, Eamonn J Dickson.

  Anomalous aggregation of α-synuclein (α-Syn) is a pathological hallmark of many degenerative synucleinopathies including Lewy body dementia (LBD) and Parkinson's disease (PD). Despite its strong link to disease, the precise molecular mechanisms that link α-Syn aggregation to neurodegeneration have yet to be elucidated. Here, we find that elevated α-Syn leads to an increase in the plasma membrane (PM) phosphoinositide PI(4,5)P2, which precipitates α-Syn aggregation and drives toxic increases in mitochondrial Ca2+ and reactive oxygen species leading to neuronal death. Upstream of this toxic signaling pathway is PIP5K1γ, whose abundance and localization is enhanced at the PM by α-Syn-dependent increases in ARF6. Selective inhibition of PIP5K1γ or knockout of ARF6 in neurons rescues α-Syn aggregation and cellular phenotypes of toxicity. Collectively, our data suggest that modulation of phosphoinositide metabolism may be a therapeutic target to slow neurodegeneration for PD and other related neurodegenerative disorders.

Keywords:  CP: Neuroscience; IP(3); PIP5K; calcium; membrane contact sites; neurodegeneration; phosphoinositide PI(4,5)P(2); α-Syn

DOI:  https://doi.org/10.1016/j.celrep.2023.113244
Nat Plants. 2023 Oct 16.

ARP2/3 complex associates with peroxisomes to participate in pexophagy in plants.

Jan Martinek, Petra Cifrová, Stanislav Vosolsobě, Judith García-González, Kateřina Malínská, Zdeňka Mauerová, Barbora Jelínková, Jana Krtková, Lenka Sikorová, Ian Leaves, Imogen Sparkes, Kateřina Schwarzerová.

Actin-related protein (ARP2/3) complex is a heteroheptameric protein complex, evolutionary conserved in all eukaryotic organisms. Its conserved role is based on the induction of actin polymerization at the interface between membranes and the cytoplasm. Plant ARP2/3 has been reported to participate in actin reorganization at the plasma membrane during polarized growth of trichomes and at the plasma membrane-endoplasmic reticulum contact sites. Here we demonstrate that individual plant subunits of ARP2/3 fused to fluorescent proteins form motile spot-like structures in the cytoplasm that are associated with peroxisomes in Arabidopsis and tobacco. ARP2/3 is found at the peroxisome periphery and contains the assembled ARP2/3 complex and the WAVE/SCAR complex subunit NAP1. This ARP2/3-positive peroxisomal domain colocalizes with the autophagosome and, under conditions that affect the autophagy, colocalization between ARP2/3 and the autophagosome increases. ARP2/3 subunits co-immunoprecipitate with ATG8f and peroxisome-associated ARP2/3 interact in vivo with the ATG8f marker. Since mutants lacking functional ARP2/3 complex have more peroxisomes than wild type, we suggest that ARP2/3 has a novel role in the process of peroxisome degradation by autophagy, called pexophagy.

DOI: https://doi.org/10.1038/s41477-023-01542-6
Plant Cell Physiol. 2023 Oct 19. pii: pcad122. [Epub ahead of print]

ATAD3 Proteins: Unique Mitochondrial Proteins Essential for Life in Diverse Eukaryotic Lineages.

Elizabeth R Waters, Magdalena Bezanilla, Elizabeth Vierling.

  ATAD3 proteins (ATPase family AAA domain-containing protein 3) are unique mitochondrial proteins that arose deep in the eukaryotic lineage but that are surprisingly absent from the Fungi and Amoebozoa. These ~600 amino acid proteins are anchored in the inner mitochondrial membrane and are essential in metazoans and Arabidopsis thaliana. ATAD3s comprise a C-terminal AAA+ matrix domain and an ATAD3_N domain that is located primarily in the inner membrane space but potentially extends into cytosol to interact with the ER. Sequence and structural alignments indicate ATAD3 proteins are most similar to classic chaperone unfoldases in AAA+ family, suggesting that they operate in mitochondrial protein quality control. A. thaliana has four ATAD3 genes in two distinct clades that appear first in the seed plants, and both clades are essential for viability. The four genes are generally coordinately expressed, and transcripts are highest in growing apices and imbibed seeds. Plants with disrupted ATAD3 have reduced growth, aberrant mitochondrial morphology, diffuse nucleoids and reduced oxidative phosphorylation complex I. These and other pleiotropic phenotypes are also observed in ATAD3 mutants in metazoans. Here we discuss the distribution of ATAD3 proteins as they have evolved in the plant kingdom, their unique structure, what we know about their function in plants, and the challenges in determining their essential roles in mitochondria.

Keywords:   Arabidopsis thaliana ; eukaryotic evolution; membrane contact sites; nucleoids; oxidative phosphorylation; protein quality control

DOI:  https://doi.org/10.1093/pcp/pcad122