bims-mecosi 2024-09-15 papers

Issue of 2024–09–15
six papers selected by
Verena Kohler, Umeå University

iScience. 2024 Sep 20. 27(9): 110683

Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.

Amelie Raby, Sonia Missiroli, Peggy Sanatine, Dominique Langui, Julien Pansiot, Nissai Beaude, Lucie Vezzana, Rachelle Saleh, Martina Marinello, Mireille Laforge, Paolo Pinton, Ana Buj-Bello, Andrea Burgo.

Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins. Here, we showed that overexpressed M1 spastin localizes in ER-mitochondria intersections and that endogenous spastin accumulates in MERCs. We demonstrated in different cellular models that downregulation of spastin enhances the number of MERCs, alters mitochondrial morphology, and impairs ER and mitochondrial calcium homeostasis. These effects are associated with reduced mitochondrial membrane potential, oxygen species levels, and oxidative metabolism. These findings extend our knowledge on the role of spastin in the ER and suggest MERCs deregulation as potential causes of SPG4-HSP disease.

Keywords: Biological sciences; Molecular biology; Molecular interaction

DOI: https://doi.org/10.1016/j.isci.2024.110683

Nat Commun. 2024 Sep 10. 15(1): 7888

Intracellular morphogenesis of diatom silica is guided by local variations in membrane curvature.

Lior Aram, Diede de Haan, Neta Varsano, James B Gilchrist, Christoph Heintze, Ron Rotkopf, Katya Rechav, Nadav Elad, Nils Kröger, Assaf Gal.

Silica cell-wall formation in diatoms is a showcase for the ability of organisms to control inorganic mineralization. The process of silicification by these unicellular algae is tightly regulated within a membrane-bound organelle, the silica deposition vesicle (SDV). Two opposing scenarios were proposed to explain the tight regulation of this intracellular process: a template-mediated process that relies on preformed scaffolds, or a template-independent self-assembly process. The present work points to a third scenario, where the SDV membrane is a dynamic mold that shapes the forming silica. We use in-cell cryo-electron tomography to visualize the silicification process in situ, in its native-state, and with a nanometer-scale resolution. This reveals that the plasma membrane interacts with the SDV membrane via physical tethering at membrane contact sites, where the curvature of the tethered side of the SDV membrane mirrors the intricate silica topography. We propose that silica growth and morphogenesis result from the biophysical properties of the SDV and plasma membranes.

DOI: https://doi.org/10.1038/s41467-024-52211-x

J Cereb Blood Flow Metab. 2024 Sep 09. 271678X241281547

Sigma-1 receptor signaling: A potential therapeutic approach for ischemic stroke.

Alex Ngo, Nikolai Fattakhov, Michal Toborek.

Strokes constitute over 50% of all neurological diseases, standing as the foremost cause of physical and mental disability. Currently, there are no widely accepted gold standard treatments for ischemic strokes beyond intravenous thrombolysis and mechanical thrombectomy applied during the acute therapeutic window. Therefore, the need for novel treatments targeting crucial signaling mediators involved in ischemic stroke is of utmost importance. The sigma-1 receptor (S1R), a molecular chaperone located at mitochondria-associated endoplasmic reticulum membranes (MAM), has exhibited neuroprotective effects when modulated by synthetic and endogenous agents across various cerebrovascular diseases. In this review, we describe the emerging therapeutic role of S1R agonists and antagonists in regulating blood-brain barrier (BBB) dysfunction, neuroinflammation, and neurocognitive impairment following ischemic stroke.

Keywords: Blood-brain barrier; agonists; antagonists; ischemic stroke; sigma-1 receptor

DOI: https://doi.org/10.1177/0271678X241281547

Biochim Biophys Acta Mol Cell Res. 2024 Sep 11. pii: S0167-4889(24)00186-1. [Epub ahead of print] 119843

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms.

Suzan Kors, Martin Schuster, Daniel C Maddison, Sreedhar Kilaru, Tina A Schrader, Joseph L Costello, Markus Islinger, Gaynor A Smith, Michael Schrader.

Acyl-CoA binding domain-containing proteins (ACBDs) perform diverse but often uncharacterised functions linked to cellular lipid metabolism. Human ACBD4 and ACBD5 are closely related peroxisomal membrane proteins, involved in tethering of peroxisomes to the ER and capturing fatty acids for peroxisomal β-oxidation. ACBD5 deficiency causes neurological abnormalities including ataxia and white matter disease. Peroxisome-ER contacts depend on an ACBD4/5-FFAT motif, which interacts with ER-resident VAP proteins. As ACBD4/5-like proteins are present in most fungi and all animals, we combined phylogenetic analyses with experimental approaches to improve understanding of their evolution and functions. Notably, all vertebrates exhibit gene sequences for both ACBD4 and ACBD5, while invertebrates and fungi possess only a single ACBD4/5-like protein. Our analyses revealed alterations in domain structure and FFAT sequences, which help understanding functional diversification of ACBD4/5-like proteins. We show that the Drosophila melanogaster ACBD4/5-like protein possesses a functional FFAT motif to tether peroxisomes to the ER via Dm_Vap33. Depletion of Dm_Acbd4/5 caused peroxisome redistribution in wing neurons and reduced life expectancy. In contrast, the ACBD4/5-like protein of the filamentous fungus Ustilago maydis lacks a FFAT motif and does not interact with Um_Vap33. Loss of Um_Acbd4/5 resulted in an accumulation of peroxisomes and early endosomes at the hyphal tip. Moreover, lipid droplet numbers increased, and mitochondrial membrane potential declined, implying altered lipid homeostasis. Our findings reveal differences between tethering and metabolic functions of ACBD4/5-like proteins across evolution, improving our understanding of ACBD4/5 function in health and disease. The need for a unifying nomenclature for ACBD proteins is discussed.

Keywords: ACBD4; ACBD5; Drosophila melanogaster; Membrane contact sites; Neurons; Organelle distribution; Peroxisomes; Ustilago maydis; VAP; Vap33

DOI: https://doi.org/10.1016/j.bbamcr.2024.119843

Cell Biochem Biophys. 2024 Sep 13.

Computational Model of Complex Calcium Dynamics: Store Operated Ca2+ Channels and Mitochondrial Associated Membranes in Pancreatic Acinar Cells.

Neeraj Manhas.

This proposed model explores the intricate Ca2+ dynamics within the pancreatic acinar cells (PACs) by emphasizing the role of store-operated Ca2+ entry (SOCE) and the mitochondrial-associated membranes (MAMs) in the secretory region (apical) of the PACs. Traditionally, Ca2+ releases from the endoplasmic reticulum (ER) via calcium-induced calcium release (CICR). It has been shown to be important in regulating functions such as secretion of digestive enzymes in PACs. However, this model posits that upon the depletion of Ca2+ in the ER, the signaling protein stromal interaction molecule (STIM1) is activated. Activated STIM1, then facilitates the opening of Orai channels, allowing Ca2+ influx through the store-operated calcium channels (SOCCs). The model highlights the complexity of the Ca2+ dynamics, and the importance of SOCE and MAMs in the PACs Ca2+ homeostasis. The numerical and bifurcation analysis illustrate how changes in agonist concentrations can lead to the diverse Ca2+ oscillation patterns, such as thin to broader oscillations, sinusoidal patterns, and baseline fluctuations, driven by the feedback mechanisms involving Ca2+ and inositol 1,4,5 trisphosphate (IP3). This understanding could have broader implications for cellular physiology and the development of therapies targeting Ca2+ signaling pathways.

Keywords: Bifurcation analysis; Calcium Oscillations; MAMs; Store-operated Ca2+ entry

DOI: https://doi.org/10.1007/s12013-024-01484-6

Bioessays. 2024 Sep 13. e2400126

Compartmentalized signaling in the soma: Coordination of electrical and protein kinase A signaling at neuronal ER-plasma membrane junctions.

Nicholas C Vierra.

Neuronal information processing depends on converting membrane depolarizations into compartmentalized biochemical signals that can modify neuronal activity and structure. However, our understanding of how neurons translate electrical signals into specific biochemical responses remains limited, especially in the soma where gene expression and ion channel function are crucial for neuronal activity. Here, I emphasize the importance of physically compartmentalizing action potential-triggered biochemical reactions within the soma. Emerging evidence suggests that somatic endoplasmic reticulum-plasma membrane (ER-PM) junctions are specialized organelles that coordinate electrical and biochemical signaling. The juxtaposition of ion channels and signaling proteins at a prominent subset of these sites enables compartmentalized calcium and cAMP-dependent protein kinase (PKA) signaling. I explore the hypothesis that these PKA-containing ER-PM junctions serve as critical sites for translating membrane depolarizations into PKA signals and identify key gaps in knowledge of the assembly, regulation, and neurobiological functions of this somatic signaling system.

Keywords: ER‐PM junctions; Kv2 channels; PKA signaling; neuronal compartmentalization

DOI: https://doi.org/10.1002/bies.202400126