title: Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome.
abstract: Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.|Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Cagalinec
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Mailis
authors.identifier: 0000-0001-6203-4810
authors.initials: M
authors.lastname: Liiv
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hodurova
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Miriam Ann
authors.identifier: 0000-0002-3363-8583
authors.initials: MA
authors.lastname: Hickey
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Annika
authors.identifier: 0000-0003-0296-8325
authors.initials: A
authors.lastname: Vaarmann
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Merle
authors.initials: M
authors.lastname: Mandel
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Akbar
authors.initials: A
authors.lastname: Zeb
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Vinay
authors.initials: V
authors.lastname: Choubey
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Malle
authors.identifier: 0000-0002-4681-1859
authors.initials: M
authors.lastname: Kuum
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Dzhamilja
authors.initials: D
authors.lastname: Safiulina
authors.affiliation: Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Eero
authors.initials: E
authors.lastname: Vasar
authors.affiliation: INSERM U-1180, Châtenay-Malabry, France.|University Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.affiliation: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Allen
authors.initials: A
authors.lastname: Kaasik
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D063306:Mitophagy / Q000235:genetics; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D059008:Time-Lapse Imaging / Q000379:methods; D014929:Wolfram Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; C114987:wolframin protein; D002118:Calcium