ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

Autor: Liiv M; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Vaarmann A; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia. annika.vaarmann@ut.ee., Safiulina D; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Choubey V; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Gupta R; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Kuum M; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Janickova L; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia.; Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Ch. du Musée 14, 1700, Fribourg, Switzerland.; Department of Cell Pharmacology and Developmental Toxicology, Institute of Experimental Pharmacology and Toxicology, Dúbravská cesta 9, 84104, Bratislava, Slovakia., Hodurova Z; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia.; Department of Cell Pharmacology and Developmental Toxicology, Institute of Experimental Pharmacology and Toxicology, Dúbravská cesta 9, 84104, Bratislava, Slovakia., Cagalinec M; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia.; Department of Cellular Cardiology, Institute of Experimental Endocrinology, Biomedical Research Center and Centre of Excellence for Advanced Materials Application, Slovak Academy of Sciences, Dúbravská cesta 9, 84505, Bratislava, Slovakia., Zeb A; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Hickey MA; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Huang YL; Department of Life Sciences, Institute of Genome Sciences and Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, 155 Li-Nong St., Section 2, Peitou, Taipei, 11221, Taiwan., Gogichaishvili N; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Mandel M; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Plaas M; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Vasar E; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia., Loncke J; Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, O&N1 Herestraat 49, Leuven, Belgium., Vervliet T; Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, O&N1 Herestraat 49, Leuven, Belgium., Tsai TF; Department of Life Sciences, Institute of Genome Sciences and Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, 155 Li-Nong St., Section 2, Peitou, Taipei, 11221, Taiwan., Bultynck G; Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, O&N1 Herestraat 49, Leuven, Belgium., Veksler V; Laboratory of Signaling and Cardiovascular Pathophysiology, Université Paris-Saclay, Inserm, UMR-S 1180, 91400, Orsay, France., Kaasik A; Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia. allen.kaasik@ut.ee.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 21; Vol. 15 (1), pp. 6143. Date of Electronic Publication: 2024 Jul 21.
DOI: 10.1038/s41467-024-50502-x
Abstrakt: Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca 2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca 2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca 2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP 3 R-mediated Ca 2+ transfer from ER to mitochondria and decreased mitochondrial Ca 2+ uptake. In turn, reduced mitochondrial Ca 2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD + ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca 2+ homeostasis, enhance mitochondrial function and improve neuronal health.
(© 2024. The Author(s).)
Databáze: MEDLINE
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