bims-mecosi 2023-08-06 papers

Issue of 2023–08–06
six papers selected by
Verena Kohler, University of Graz

Curr Opin Cell Biol. 2023 Jul 27. pii: S0955-0674(23)00061-3. [Epub ahead of print]83 102212

Piecing together the structural organisation of lipid exchange at membrane contact sites.

Membrane contact sites (MCSs) are areas of close proximity between organelles, implicated in transport of small molecules and in organelle biogenesis. Lipid transfer proteins at MCSs facilitate the distribution of lipid species between organelle membranes. Such exchange processes rely on the apposition of two different membranes delimiting distinct compartments and a cytosolic intermembrane space. Maintaining organelle identity while transferring molecules therefore implies control over MCS architecture both on the ultrastructural and molecular levels. Factors including intermembrane distance, density of resident proteins, and contact surface area fine-tune MCS function. Furthermore, the structural arrangement of lipid transfer proteins and associated proteins underpins the molecular mechanisms of lipid fluxes at MCSs. Thus, the architecture of MCSs emerges as an essential aspect of their function.

DOI: https://doi.org/10.1016/j.ceb.2023.102212

Front Oncol. 2023 ;13 1217741

Ultrastructural analysis of prostate cancer tissue provides insights into androgen-dependent adaptations to membrane contact site establishment.

Lisa M Butler, Emma Evergren.

Membrane trafficking and organelle contact sites are important for regulating cell metabolism and survival; processes often deregulated in cancer. Prostate cancer is the second leading cause of cancer-related death in men in the developed world. While early-stage disease is curable by surgery or radiotherapy there is an unmet need to identify prognostic biomarkers, markers to treatment response and new therapeutic targets in intermediate-late stage disease. This study explored the morphology of organelles and membrane contact sites in tumor tissue from normal, low and intermediate histological grade groups. The morphology of organelles in secretory prostate epithelial cells; including Golgi apparatus, ER, lysosomes; was similar in prostate tissue samples across a range of Gleason scores. Mitochondrial morphology was not dramatically altered, but the number of membrane contacts with the ER notably increased with disease progression. A three-fold increase of tight mitochondria-ER membrane contact sites was observed in the intermediate Gleason score group compared to normal tissue. To investigate whether these changes were concurrent with an increased androgen signaling in the tissue, we investigated whether an anti-androgen used in the clinic to treat advanced prostate cancer (enzalutamide) could reverse the phenotype. Patient-derived explant tissues with an intermediate Gleason score were cultured ex vivo in the presence or absence of enzalutamide and the number of ER-mitochondria contacts were quantified for each matched pair of tissues. Enzalutamide treated tissue showed a significant reduction in the number and length of mitochondria-ER contact sites, suggesting a novel androgen-dependent regulation of these membrane contact sites. This study provides evidence for the first time that prostate epithelial cells undergo adaptations in membrane contact sites between mitochondria and the ER during prostate cancer progression. These adaptations are androgen-dependent and provide evidence for a novel hormone-regulated mechanism that support establishment and extension of MAMs. Future studies will determine whether these changes are required to maintain pro-proliferative signaling and metabolic changes that support prostate cancer cell viability.

Keywords: androgen-deprivation; lipophagy; membrane-contact site; mitochondria-associated membrane; patient-derived tumor explant

DOI: https://doi.org/10.3389/fonc.2023.1217741

Proc Natl Acad Sci U S A. 2023 Aug 08. 120(32): e2303402120

Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66.

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca2+ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca2+ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1-PACS2-PKD2 complex, regulating PKD2-dependent mitochondrial Ca2+ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca2+ uptake and the dramatic increase of the cytosolic Ca2+ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca2+-dependent neurotransmitter release.

Keywords: calcium; casein kinase 2; developmental and epileptic encephalopathy-66; mitochondria-associated ER membranes

DOI: https://doi.org/10.1073/pnas.2303402120

iScience. 2023 Jul 21. 26(7): 107180

Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.

Hema Saranya Ilamathi, Sara Benhammouda, Amel Lounas, Khalid Al-Naemi, Justine Desrochers-Goyette, Matthew A Lines, François J Richard, Jackie Vogel, Marc Germain.

Mitochondria are multifaceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) replication is a spatially regulated process essential for the maintenance of mitochondrial function, its defect causing mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is affected by mitochondrial dynamics: The absence of mitochondrial fusion is associated with mtDNA depletion whereas loss of mitochondrial fission causes the aggregation of mtDNA within abnormal structures termed mitobulbs. Here, we show that contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and distribution within mitochondrial networks. DRP1 loss or mutation leads to modified ER sheets and alters the interaction between ER sheets and mitochondria, disrupting RRBP1-SYNJ2BP interaction. Importantly, mtDNA distribution and replication were rescued by promoting ER sheets-mitochondria contact sites. Our work identifies the role of ER sheet-mitochondria contact sites in regulating mtDNA replication and distribution.

Keywords: Biochemistry; Biological sciences; Cell biology

DOI: https://doi.org/10.1016/j.isci.2023.107180

Adv Drug Deliv Rev. 2023 Jul 27. pii: S0169-409X(23)00340-X. [Epub ahead of print] 115025

Targeted to neuronal organelles for CNS drug development.

Zheng Ying, Na Ye, Qilian Ma, Fan Chen, Ningning Li, Xuechu Zhen.

Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug targets displaying great therapeutic potential. Although the basic biological mechanism underlying the dynamics of intracellular organelles has been extensively studied, relative drug development is still limited. In the present review, we show that due to the development of technical advanced imaging tools, especially live cell imaging methods, intracellular organelle dynamics (including mitochondrial dynamics and membrane contact sites) can be dissected at the molecular level. Based on these identified molecular targets, we review and discuss the potential of drug development to target organelle dynamics, especially mitochondria dynamics and ER-organelle membrane contact dynamics, in the central nervous system for treating human diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Keywords: endoplasmic reticulum; membrane contact sites; mitochondria; neurodegeneration; σ(1)R

DOI: https://doi.org/10.1016/j.addr.2023.115025

EMBO J. 2023 Jul 31. e111252

RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.

Tom Cremer, Lenard M Voortman, Erik Bos, Marlieke Lm Jongsma, Laurens R Ter Haar, Jimmy Jll Akkermans, Cami Mp Talavera Ormeño, Ruud Hm Wijdeven, Jelle de Vries, Robbert Q Kim, George Mc Janssen, Peter A van Veelen, Roman I Koning, Jacques Neefjes, Ilana Berlin.

Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER-embedded RING finger protein 26 (RNF26) at the C-terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis.

Keywords: ER stress; ERphagy; RNF26; endolysosomes; intermediate filaments

DOI: https://doi.org/10.15252/embj.2022111252