bims-mecosi 2025-01-05 papers

Issue of 2025–01–05
three papers selected by
Verena Kohler, Umeå University

Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241305593

Channels, Transporters, and Receptors at Membrane Contact Sites.

Membrane contact sites (MCSs) are specialized regions where two or more organelle membranes come into close apposition, typically separated by only 10-30 nm, while remaining distinct and unfused. These sites play crucial roles in cellular homeostasis, signaling, and metabolism. This review focuses on ion channels, transporters, and receptors localized to MCSs, with particular emphasis on those associated with the plasma membrane and endoplasmic reticulum (ER). We discuss the molecular composition and functional significance of these proteins in shaping both organelle and cellular functions, highlighting their importance in excitable cells and their influence on intracellular calcium signaling. Key MCSs examined include ER-plasma membrane, ER-mitochondria, and ER-lysosome contacts. This review addresses our current knowledge of the ion channels found within these contacts, the dynamic regulation of MCSs, their importance in various physiological processes, and their potential implications in pathological conditions.

Keywords: IP3 receptor; calcium (Ca2+); calcium-induced calcium release (CICR); endoplasmic reticulum (ER); ion channels; junctophilin (JPH); large conductance Ca2+-activated K+ channel (BKCa); membrane contact sites (MCS); neurodegeneration; niemann-Pick type C1 (NPC1); orai; ryanodine receptors (RyR); stromal interaction molecule (Stim); transient receptor potential cation channel subfamily M member 4 (TRPM4); voltage-gated calcium channel (CaV); voltage-gated potassium channel (KV)

DOI: https://doi.org/10.1177/25152564241305593

Sci Rep. 2025 Jan 02. 15(1): 325

Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.

Raffaele Pastore, Lihang Yao, Nathan Hatcher, Martin Helley, Janet Brownlees, Radha Desai.

Dysfunction of the endo-lysosomal intracellular Cholesterol transporter 2 protein (NPC2) leads to the onset of Niemann-Pick Disease Type C (NPC), a lysosomal storage disorder. Metabolic and homeostatic mechanisms are disrupted in lysosomal storage disorders (LSDs) hence we characterized a cellular model of NPC2 knock out, to assess alterations in organellar function and inter-organellar crosstalk between mitochondria and lysosomes. We performed characterization of lipid alterations and confirmed altered lysosomal morphology, but no overt changes in oxidative stress markers. Using several techniques, we demonstrated that contacts between mitochondria and late endosomes/lysosomes are reduced in NPC2-/- HEK cells, we observed that the acidic compartments are swollen and lipid dense. Quantification of endogenous lipids in HEKNPC2-/- cells by mass spectrometry reveals accumulation of lipid species indicative of sphingolipid metabolic dysregulation within the lysosome. Specifically, HEK NPC2-/- cells exhibit marked elevation of glucosylsphingosine and glucosylceramides, substrates of beta glucocerebroside (GBA), as well as accumulation of sphingosine and sphingomyelins. Our studies suggest an involvement of NPC2 in the formation of contact sites between mitochondria and lysosomes and support the hypothesis of a role for NPC2 in the endo-lysosomal trafficking pathway and dynamic organellar crosstalk.

DOI: https://doi.org/10.1038/s41598-024-83460-x

Sci Rep. 2024 Dec 30. 14(1): 31783

HMGCS2 and AMACR as potential targets linking mitochondrial dysfunction and ulcerative colitis.

Rui Zhu, Xinyu Bai, Zhangqin Li, Hao Liang, Huixian Song, Lifang Chen, Yinglei Miao, Fengrui Zhang, Junkun Niu.

Ulcerative colitis (UC) is characterised notably by an imbalance in intestinal mucosal homeostasis. Although mitochondrial dysfunction has been identified as a potential contributor to this imbalance, it remains an incomplete understanding. Consequently, further investigation into the role of mitochondria in UC is warranted. The study focusing on the GSE87466 dataset for differential gene expression analysis. Mitochondria-related genes were sourced from the MitoCart3.0 database. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify hub genes. The intersection of DEGs, hub genes, and mitochondria-related genes facilitated the identification of 14 mitochondria-related differentially expressed genes (MitoDEGs). Three machine learning algorithms were then applied to select signature MitoDEGs specific to UC: HMGCS2 and AMACR. They have decreased expression in UC patients and have a high diagnostic value for UC. In the inflammatory environment, knockout of both HMGCS2 and AMACR showed disruption of mitochondrial structure and function. Among them, the AMACR knockdown group had an increased number of damaged mitochondria and a significant reduction in the length, area and circumference of MAMs. Therefore, the study identified two new signature MitoDEGs in UC. HMGCS2 and AMACR provide insights into the interplay between mitochondrial dysfunction and UC intestinal mucosal homeostasis.

Keywords: Immune infiltration; Machine learning; Mitochondria; Ulcerative colitis; WGCNA

DOI: https://doi.org/10.1038/s41598-024-82900-y