bims-mecosi 2024-10-06 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2024‒10‒06
ten papers selected by
Verena Kohler, Umeå University

Mitochondria, Peroxisomes and Beyond-How Dual Targeting Regulates Organelle Tethering.
ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.
Biogenesis of mitochondrial β-barrel membrane proteins.
Altered Endoplasmic Reticulum Integrity and Organelle Interactions in Living Cells Expressing INF2 Variants.
Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
Human Salivary Histatin 1 Regulating IP3R1/GRP75/VDAC1 Mediated Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAMs) Inhibits Cell Senescence For Diabetic Wound Repair.
Insights into the Role of VPS39 and Its Interaction with CP204L and A137R in ASFV Infection.
Attenuation of PM2.5-Induced Lung Injury by 4-Phenylbutyric Acid: Maintenance of [Ca2+]i Stability between Endoplasmic Reticulum and Mitochondria.
Eicosatrienoic acid enhances the quality of in vitro matured porcine oocytes by reducing PRKN-mediated ubiquitination of CISD2.
Lipid Droplets Big and Small: Basic Mechanisms That Make Them All.

Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241264254

Mitochondria, Peroxisomes and Beyond-How Dual Targeting Regulates Organelle Tethering.

Johannes Freitag, Thorsten Stehlik, Gert Bange.

  Eukaryotic cells feature distinct membrane-enclosed organelles such as mitochondria and peroxisomes, each playing vital roles in cellular function and organization. These organelles are linked at membrane contact sites, facilitating interorganellar molecule and ion exchange. Most contact-forming proteins identified to date are membrane proteins or membrane-associated proteins, which can form very stable contacts. Recent findings suggest additional mechanistically distinct tethering events that arise from dual protein targeting. Proteins bearing targeting signals for multiple organelles, such as an N-terminal signal for mitochondria and a C-terminal signal for peroxisomes, function as tethers, fostering contacts by engaging targeting factors at both organelles. A number of dually targeted membrane proteins can contribute to contact site formation and transit from one organelle to the other as well. These interactions may enable the fine-tuning of organelle proximity, hence, adapting connections to meet varying physiological demands.

Keywords:  dual targeting; mitochondrion; peroxisome; protein trafficking; targeting signal; tether

DOI:  https://doi.org/10.1177/25152564241264254
Cell Commun Signal. 2024 Sep 30. 22(1): 464

ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.

Ying-Jia Chi, Zhen-Yu Bai, Guang-Li Feng, Xiao-Hong Lai, Yu-Feng Song.

  BACKGROUND: Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver.METHODS: In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments.
RESULTS: The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs's structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals.
CONCLUSIONS: The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.

Keywords:  Ca2+ Signaling; ER-mitochondria contact sites (MERCs); Hepatic lipogenesis; Ip3r-Grp75-Vdac; Seipin

DOI:  https://doi.org/10.1186/s12964-024-01829-x
FEBS Open Bio. 2024 Oct;14(10): 1595-1609

Biogenesis of mitochondrial β-barrel membrane proteins.

Iniyan Ganesan, Jon V Busto, Nikolaus Pfanner, Nils Wiedemann.

  β-barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β-barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β-barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β-barrel protein. The β-strands of β-barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50-preprotein hybrid barrel. The assembled precursor β-barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β-barrel, termed the β-barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer-to-inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER-mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β-barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.

Keywords:  Mco6; Mdm10; SAM; Sam35; Sam37; Sam50; mitochondria; outer membrane; sorting and assembly machinery; β‐barrel protein

DOI:  https://doi.org/10.1002/2211-5463.13905
Int J Mol Sci. 2024 Sep 10. pii: 9783. [Epub ahead of print]25(18):

Altered Endoplasmic Reticulum Integrity and Organelle Interactions in Living Cells Expressing INF2 Variants.

Quynh Thuy Huong Tran, Naoyuki Kondo, Hiroko Ueda, Yoshiyuki Matsuo, Hiroyasu Tsukaguchi.

  The cytoskeleton mediates fundamental cellular processes by organizing inter-organelle interactions. Pathogenic variants of inverted formin 2 (INF2) CAAX isoform, an actin assembly factor that is predominantly expressed in the endoplasmic reticulum (ER), are linked to focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth (CMT) neuropathy. To investigate how pathogenic INF2 variants alter ER integrity, we used high-resolution live imaging of HeLa cells. Cells expressing wild-type (WT) INF2 showed a predominant tubular ER with perinuclear clustering. Cells expressing INF2 FSGS variants that cause mild and intermediate disease induced more sheet-like ER, a pattern similar to that seen for cells expressing WT-INF2 that were treated with actin and microtubule (MT) inhibitors. Dual CMT-FSGS INF2 variants led to more severe ER dysmorphism, with a diffuse, fragmented ER and coarse INF2 aggregates. Proper organization of both F-actin and MT was needed to modulate the tubule vs. sheet conformation balance, while MT arrays regulated spatial expansion of tubular ER in the cell periphery. Pathogenic INF2 variants also induced mitochondria fragmentation and dysregulated mitochondria distribution. Such mitochondrial abnormalities were more prominent for cells expressing CMT-FSGS compared to those with FSGS variants, indicating that the severity of the dysfunction is linked to the degree of cytoskeletal disorganization. Our observations suggest that pathogenic INF2 variants disrupt ER continuity by altering interactions between the ER and the cytoskeleton that in turn impairs inter-organelle communication, especially at ER-mitochondria contact sites. ER continuity defects may be a common disease mechanism involved in both peripheral neuropathy and glomerulopathy.

Keywords:  cytoskeleton; endoplasmic reticulum; glomerulosclerosis; mitochondria; podocyte

DOI:  https://doi.org/10.3390/ijms25189783
Cell Rep. 2024 Sep 28. pii: S2211-1247(24)01145-8. [Epub ahead of print]43(10): 114794

Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.

Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.

  Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.

Keywords:  CP: Cell biology; CP: Metabolism; Ca(2+); ER-mitochondrial contact; LBR; VDAC2; cell cycle; cell division; energy generation; metaphase-anaphase transition; mitochondria; mitosis

DOI:  https://doi.org/10.1016/j.celrep.2024.114794
Free Radic Biol Med. 2024 Sep 27. pii: S0891-5849(24)00693-2. [Epub ahead of print]

Human Salivary Histatin 1 Regulating IP3R1/GRP75/VDAC1 Mediated Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAMs) Inhibits Cell Senescence For Diabetic Wound Repair.

Tinghui Xian, Yi Liu, Yongsheng Ye, Bohua Peng, Jie Huang, Lin Liang, Jiaqing Zhang, Hao Wu, Zhen Lin.

  RATIONALE: Difficulty in skin wound healing is a concern for diabetic patients across the world. Impaired mitochondrial dysfunction and aging-related vascular dysfunction in human umbilical vein endothelial cells (HUVECs) caused by oxidative stress are major impediments to diabetic wound healing. However, research on skin repair at the mechanistic level by improving mitochondrial function and inhibiting oxidative stress-induced HUVEC senescence remains lacking.METHODS AND RESULTS: Human saliva effectively inhibits the natural aging of HUVECs through immunodepletion experiments. Histatin 1 (Hst1), a short peptide comprising 38 amino acids, is the primary component of human saliva that prevents HUVEC aging. Based on in vitro findings, Hst1 decreased staining for senescence-associated β-galactosidase activity and expression of mediators of senescence signaling, including p53, p21, and p16. Mechanistically, HUVEC senescence is associated with Hst1-modulated nuclear factor Nrf2 signaling as Hst1 induces ERK-mediated Nrf2 nuclear translocation through NADPH oxidase-dependent ROS regulation, reinforced Nrf2 antioxidant response, and suppressed oxidative stress. RNA sequencing identified that the mitochondrial-related gene set was enriched in the Hst1 group. Coimmunoprecipitation indicated that Hst1 delayed hydrogen peroxide-induced HUVEC senescence by inhibiting mitochondria-associated endoplasmic reticulum (ER) membrane formation mediated by inositol 1,4,5-trisphosphate receptor 1-glucose-regulated protein 75-voltage-dependent anion channel 1 (VDAC1) complex interactions. Furthermore, in aging HUVECs, Hst1 treatment or VDAC1 silencing with small interfering RNA hindered calcium (Ca2+) transfer from the ER to the mitochondria, thereby ameliorating mitochondrial Ca2+ overload and restoring mitochondrial function. In an in vivo mouse model of diabetes mellitus skin defects, Hst1 facilitated wound healing by stimulating the new blood vessel formation and impeding the expression of senescent biomarkers.
CONCLUSIONS: This study proposes a theoretical solution that Hst1 can restore mitochondrial function by inhibiting oxidative stress or cellular senescence, thereby promoting angiogenesis and diabetic wound repair.

Keywords:  Cell senescence; Hst1; IP3R1/GRP75/VDAC1 complex; Mitochondria-associated ER membranes; Mitochondrial function; Oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.046
Viruses. 2024 Sep 17. pii: 1478. [Epub ahead of print]16(9):

Insights into the Role of VPS39 and Its Interaction with CP204L and A137R in ASFV Infection.

Katarzyna Magdalena Dolata, Axel Karger.

  The African swine fever virus (ASFV) is a large and complex DNA virus that causes a highly lethal disease in swine, for which no antiviral drugs or vaccines are currently available. Studying viral-host protein-protein interactions advances our understanding of the molecular mechanisms underlying viral replication and pathogenesis and can facilitate the discovery of antiviral therapeutics. In this study, we employed affinity tagging and purification mass spectrometry to characterize the interactome of VPS39, an important cellular factor during the early phase of ASFV replication. The interaction network of VPS39 revealed associations with mitochondrial proteins involved in membrane contact sites formation and cellular respiration. We show that the ASFV proteins CP204L and A137R target VPS39 by interacting with its clathrin heavy-chain functional domain. Furthermore, we elaborate on the potential mechanisms by which VPS39 may contribute to ASFV replication and prioritize interactions for further investigation into mitochondrial protein function in the context of ASFV infection.

Keywords:  A137R; CP204L; VPS39; african swine fever virus; protein–protein interaction; virus–host interaction

DOI:  https://doi.org/10.3390/v16091478
Biomolecules. 2024 Sep 08. pii: 1135. [Epub ahead of print]14(9):

Attenuation of PM2.5-Induced Lung Injury by 4-Phenylbutyric Acid: Maintenance of [Ca2+]i Stability between Endoplasmic Reticulum and Mitochondria.

Zhenhua Ma, Xiaohui Du, Yize Sun, Yunna Jia, Xiaojun Liang, Yunhang Gao.

  Fine particulate matter (PM2.5) is a significant cause of respiratory diseases and associated cellular damage. The mechanisms behind this damage have not been fully explained. This study investigated two types of cellular damage (inflammation and pyroptosis) induced by PM2.5, focusing on their relationship with two organelles (the endoplasmic reticulum and mitochondria). Animal models have demonstrated that PM2.5 induces excessive endoplasmic reticulum stress (ER stress), which is a significant cause of lung damage in rats. This was confirmed by pretreatment with an ER stress inhibitor (4-Phenylbutyric acid, 4-PBA). We found that, in vitro, the intracellular Ca2+ ([Ca2+]i) dysregulation induced by PM2.5 in rat alveolar macrophages was associated with ER stress. Changes in mitochondria-associated membranes (MAMs) result in abnormal mitochondrial function. This further induced the massive expression of NLRP3 and GSDMD-N, which was detrimental to cell survival. In conclusion, our findings provide valuable insights into the relationship between [Ca2+]i dysregulation, mitochondrial damage, inflammation and pyroptosis under PM2.5-induced ER stress conditions. Their interactions ultimately have an impact on respiratory health.

Keywords:  4-PBA; ER stress; PM2.5; intracellular Ca2+; mitochondrial damage; pyroptosis

DOI:  https://doi.org/10.3390/biom14091135
Theriogenology. 2024 Sep 24. pii: S0093-691X(24)00389-3. [Epub ahead of print]230 285-298

Eicosatrienoic acid enhances the quality of in vitro matured porcine oocytes by reducing PRKN-mediated ubiquitination of CISD2.

Zhi-Yong An, Sheng-Zhong Han, Zhou-Yan Li, Shuang-Yan Chang, Xiu-Li Zhang, Gao-Jie Lu, Tuo Zhang, Biao-Hu Quan, Xi-Jun Yin, Lin-Hu Quan, Jin-Dan Kang.

  Oocytes and early embryos are exposed to many uncontrollable factors that trigger endoplasmic reticulum (ER) stress during in vitro culture. Prevention of ER stress is an effective way to improve the oocyte maturation rate and oocyte quality. Increasing evidence suggests that dietary intake of sufficient n-3 polyunsaturated fatty acids (PUFAs) is associated with health benefits, particularly in the domain of female reproductive health. We found that supplementation of eicosatrienoic acid (ETA) during in vitro maturation (IVM) of oocyte significantly downregulated ER stress-related genes. Mitochondria-associated membranes (MAMs) are communications areas between the ER and mitochondria. Inositol 1,4,5-trisphosphate receptor (IP3R) is a key calcium channels in MAMs and, participates in the regulation of many cellular functions. Notably, the MAM area was significantly decreased in ETA-treated oocytes. CDGSH iron sulfur domain 2 (CISD2) is presents in MAMs, but its role in oocytes is unknown. ETA treatment significantly increased CISD2 expression, and siRNA-mediated knockdown of CISD2 blocked the inhibitory effect of ETA on IP3R. Transcriptomic sequencing and immunoprecipitation experiments showed that ETA treatment significantly decreased expression of the E3 ubiquitin ligase PRKN. PRKN induced ubiquitination and degradation of CISD2, indicating that the PRKN-mediated ubiquitin-proteasome system regulates CISD2. In conclusion, our study reveals the mechanism by which ETA supplementation during IVM alleviates mitochondrial calcium overload under ER stress conditions by decreasing PRKN-mediated ubiquitination of CISD2 and facilitating inhibition of IP3R by CISD2/BCL-2. This improves oocyte quality and subsequent embryo developmental competence prior to implantation.

Keywords:  Calcium; ETA; Endoplasmic reticulum stress; IP3R; MAM; Ubiquitin

DOI:  https://doi.org/10.1016/j.theriogenology.2024.09.020
Annu Rev Cell Dev Biol. 2024 Oct;40(1): 143-168

Lipid Droplets Big and Small: Basic Mechanisms That Make Them All.

Robin W Klemm, Pedro Carvalho.

  Lipid droplets (LDs) are dynamic storage organelles with central roles in lipid and energy metabolism. They consist of a core of neutral lipids, such as triacylglycerol, which is surrounded by a monolayer of phospholipids and specialized surface proteins. The surface composition determines many of the LD properties, such as size, subcellular distribution, and interaction with partner organelles. Considering the diverse energetic and metabolic demands of various cell types, it is not surprising that LDs are highly heterogeneous within and between cell types. Despite their diversity, all LDs share a common biogenesis mechanism. However, adipocytes have evolved specific adaptations of these basic mechanisms, enabling the regulation of lipid and energy metabolism at both the cellular and organismal levels. Here, we discuss recent advances in the understanding of both the general mechanisms of LD biogenesis and the adipocyte-specific adaptations controlling these fascinating organelles.

Keywords:  LD; LD biogenesis; LD contact sites; LD heterogeneity; LD protein targeting; LD size control; adipocyte; lipid droplet

DOI:  https://doi.org/10.1146/annurev-cellbio-012624-031419