bims-mecosi 2024-12-29 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2024–12–29
seven papers selected by
Verena Kohler, Umeå University

The Vacuole Lipid Droplet Contact Site vCLIP.
Stabilization of mitochondria-associated endoplasmic reticulum membranes regulates Aβ generation in a three-dimensional neural model of Alzheimer's disease.
Novel exploitation of autophagy by tombusviruses.
Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families.
Melodinines J Induces Apoptosis in Temozolomide-Resistant Glioma Cells by Disrupting TMX1-Dependent Homeostasis of Endoplasmic Reticulum-Mitochondria-Associated Membrane Contacts.
How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.
The endoplasmic reticulum as a cradle for virus and extracellular vesicle secretion.

Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241308722

The Vacuole Lipid Droplet Contact Site vCLIP.

Duy Trong Vien Diep, Maria Bohnert.

  Lipid droplets frequently form contact sites with the membrane of the vacuole, the lysosome-like organelle in yeast. These vacuole lipid droplet (vCLIP) contact sites respond strongly to metabolic cues: while only a subset of lipid droplets is bound to the vacuole when nutrients are abundant, other metabolic states induce stronger contact site formation. Physical lipid droplet-vacuole binding is related to the process of lipophagy, a lipid droplet-specific form of microautophagy. The molecular basis for the formation and function of vCLIP contact sites remained enigmatic for a long time. This knowledge gap was filled when it was found that vCLIP is formed by the structurally related lipid droplet tether proteins Ldo16 and Ldo45, and the vacuolar surface protein Vac8. Ldo45 additionally recruits the phosphatidylinositol transfer protein Pdr16 to vCLIP. Here, we review the literature on the lipid droplet-vacuole contact site in light of the progress in our understanding of its molecular basis and discuss future directions for the field.

Keywords:  LDAF1; Ldo16; Ldo45; Pdr16; Vac8; contact site; lipid droplet; lipophagy; lysosome; seipin; vCLIP; vacuole

DOI:  https://doi.org/10.1177/25152564241308722
Alzheimers Dement. 2024 Dec 23.

Stabilization of mitochondria-associated endoplasmic reticulum membranes regulates Aβ generation in a three-dimensional neural model of Alzheimer's disease.

Jacob C Zellmer, Marina B Tarantino, Michelle Kim, Selene Lomoio, Masato Maesako, György Hajnóczky, Raja Bhattacharyya.

   INTRODUCTION: We previously demonstrated that regulating mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) affects axonal Aβ generation in a well-characterized three-dimensional (3D) neural Alzheimer's disease (AD) model. MAMs vary in thickness and length, impacting their functions. Here, we examined the effect of MAM thickness on Aβ in our 3D neural model of AD.
METHODS: We employed fluorescence resonance energy transfer (FRET) or fluorescence-based MAM stabilizers, electron microscopy, Aβ enzyme-linked immunosorbent assay (ELISA), and live-cell imaging with kymography to assess how stabilizing MAMs of different gap widths influence Aβ production and MAM axonal mobility.
RESULTS: Stabilizing tight MAMs (∼6 nm gap width) significantly increased Aβ levels, whereas basal (∼25 nm) and loose MAMs (∼40 nm) maintained or reduced Aβ levels, respectively. Tight MAMs reduced mitochondrial axonal velocity compared to basal MAMs, while loose MAMs showed severely reduced axonal distribution.
DISCUSSION: Our findings suggest that stabilizing MAMs of specific gap widths, particularly in axons, without complete destabilization could be an effective therapeutic strategy for AD.
HIGHLIGHTS: The stabilization of MAMs exacerbates or ameliorates Aβ generation from AD neurons in a MAM gap width-dependent manner. A specific stabilization threshold within the MAM gap width spectrum shifts the amyloidogenic process to non-amyloidogenic. Tight MAMs slow down mitochondrial axonal transport compared to lose MAMs offering a quantitative method for measuring MAM stabilization.

Keywords:  Alzheimer's disease; amyloid β; endoplasmic reticulum; mitochondria; mitochondria‐associated ER membranes; β‐amyloid precursor protein; β‐site APP cleaving enzyme

DOI:  https://doi.org/10.1002/alz.14417
Virology. 2024 Dec 17. pii: S0042-6822(24)00387-8. [Epub ahead of print]603 110363

Novel exploitation of autophagy by tombusviruses.

Peter D Nagy, Judit Pogany, Yuanrong Kang.

  Positive-strand (+)RNA viruses are major pathogens of humans, animals and plants. This review summarizes the complex interplay between the host autophagy pathway and Tomato bushy stunt virus (TBSV) replication. Recent discoveries with TBSV have revealed virus-driven exploitation of autophagy in multiple ways that contributes to the unique phospholipid composition of viral replication organellar (VROs) membranes. Viral replication protein-driven subversion of phagophore membranes, recruitment of ATG2 bulk lipid transfer protein to enrich phosphatidylethanolamine and phosphatidylserine in VROs, recruitment of VPS34 PI3K to produce PI(3)P; and ATG11-facilitated formation of stable viral membrane contact sites contributes to VRO membrane proliferation. Recruitment of autophagy core proteins to vir-NBR1 bodies within vir-condensates associated with VROs results in dampened antiviral degradation by autophagy. Overall, TBSV intricate interplay with the autophagy machinery highlights the importance of lipid dynamics in viral life cycles and points toward potential directions for therapeutic intervention.

Keywords:  Dependency factor; Host factor; Lipid transfer protein; Nicotiana benthamiana; Phospholipids; Replication; Tomato bushy stunt virus; Virus-host interaction; Yeast

DOI:  https://doi.org/10.1016/j.virol.2024.110363
Nat Struct Mol Biol. 2024 Dec 23.

Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families.

Lily Yeh Jan, Yuh Nung Jan.

Calcium (Ca2+)-activated ion channels and lipid scramblases in the transmembrane protein 16 (TMEM16) family are structurally related to mechanosensitive ion channels in the TMEM63 and transmembrane channel-like (TMC) families. Members of this structurally related superfamily share similarities in gating transitions and serve a wide range of physiological functions, which is evident from their disease associations. The TMEM16, TMEM63 and TMC families include members with important functions in the cell membrane and/or intracellular organelles such as the endoplasmic reticulum, membrane contact sites, endosomes and lysosomes. Moreover, some members of the TMEM16 family and the TMC family perform dual functions of ion channel and lipid scramblase, leading to intriguing physiological implications. In addition to their physiological functions such as mediating phosphatidylserine exposure and facilitation of extracellular vesicle generation and cell fusion, scramblases are involved in the entry and replication of enveloped viruses. Comparisons of structurally diverse scramblases may uncover features in the lipid-scrambling mechanisms that are likely shared by scramblases.

DOI: https://doi.org/10.1038/s41594-024-01444-x
Phytother Res. 2024 Dec 23.

Melodinines J Induces Apoptosis in Temozolomide-Resistant Glioma Cells by Disrupting TMX1-Dependent Homeostasis of Endoplasmic Reticulum-Mitochondria-Associated Membrane Contacts.

Fanfan Chen, Weiwei Cao, Xuejuan Li, Zebin Chen, Guoxu Ma, Sicen Wang, Zongyang Li, Lei Chen, Weiping Li, Xiangbao Meng, Guodong Huang, Ping Cui.

  Glioma is recognized as one of the most lethal and aggressive brain tumors. Although the standard-of-care treatment for glioblastoma (GBM) involves maximal surgical resection and temozolomide (TMZ) chemotherapy, the discovery of novel anti-tumor agents from nature sources is an effective strategy for glioma treatment. In this study, we conducted a screening process to identify the bisindole alkaloid melodinine J (MDJ) from Melodinus tenuicaudatus. We assessed its potency in overcoming TMZ resistance in patient-derived recurrent glioma strains, TMZ-resistant cell lines, and nude mouse tumor models of glioma cells. Our results first indicated that MDJ effectively inhibited malignancy and stimulated apoptosis in glioma. Mechanistic studies revealed that MDJ triggered deadly mitochondrial dysfunction and apoptosis by disrupting cross-organellar communication between the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). We also showed that high levels of TMX1 may promote malignancy of glioma by ER-mitochondria communications, bioenergetics efficiency, and tumor growth. Overall, our study proved that MDJ interfered the function of TMX1-mediated MAM networks, thereby overcoming the proliferation and chemo-resistance of glioma cells.

Keywords:  ER and mitochondria‐associated membranes; TMX1; chemotherapy resistance; glioma; melodinine J

DOI:  https://doi.org/10.1002/ptr.8396
Exp Eye Res. 2024 Dec 22. pii: S0014-4835(24)00441-X. [Epub ahead of print]251 110219

How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.

Aparna Lakkaraju, Patricia Boya, Marie Csete, Deborah A Ferrington, James B Hurley, Alfredo A Sadun, Peng Shang, Ruchi Sharma, Debasish Sinha, Marius Ueffing, Susan E Brockerhoff.

  Organelles such as mitochondria, lysosomes, peroxisomes, and the endoplasmic reticulum form highly dynamic cellular networks and exchange information through sites of physical contact. While each organelle performs unique functions, this inter-organelle crosstalk helps maintain cell homeostasis. Age-related macular degeneration (AMD) is a devastating blinding disease strongly associated with mitochondrial dysfunction, oxidative stress, and decreased clearance of cellular debris in the retinal pigment epithelium (RPE). However, how these occur, and how they relate to organelle function both with the RPE and potentially the photoreceptors are fundamental, unresolved questions in AMD biology. Here, we report the discussions of the "Mitochondria, Lysosomes, and other Organelle Interactions" task group of the 2024 Ryan Initiative for Macular Research (RIMR). Our group focused on understanding the interplay between cellular organelles in maintaining homeostasis in the RPE and photoreceptors, how this could be derailed to promote AMD, and identifying where these pathways could potentially be targeted therapeutically.

Keywords:  Bioenergetics; Oxidative stress; Photoreceptors; Retinal pigment epithelium; Therapeutics

DOI:  https://doi.org/10.1016/j.exer.2024.110219
Trends Cell Biol. 2024 Dec 26. pii: S0962-8924(24)00250-2. [Epub ahead of print]

The endoplasmic reticulum as a cradle for virus and extracellular vesicle secretion.

Yonis Bare, Kyra Defourny, Marine Bretou, Guillaume Van Niel, Esther Nolte-'t Hoen, Raphael Gaudin.

  Extracellular vesicles (EVs) are small membranous carriers of protein, lipid, and nucleic acid cargoes and play a key role in intercellular communication. Recent work has revealed the previously under-recognized participation of endoplasmic reticulum (ER)-associated proteins (ERAPs) during EV secretion, using pathways reminiscent of viral replication and secretion. Here, we present highlights of the literature involving ER/ERAPs in EV biogenesis and propose mechanistic parallels with ERAPs exploited during viral infections. We propose that ERAPs play an active role in the release of EVs and viral particles, and we present views on whether viruses hijack or enhance pre-existing ERAP-dependent secretory machineries or whether they repurpose ERAPs to create new secretory pathways.

Keywords:  exocytosis; membrane contact sites; secretory autophagy; viral infection; virus assembly; virus release

DOI:  https://doi.org/10.1016/j.tcb.2024.11.008