Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome.
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...
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2016-07-01
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doaj-cc6c71332b70484f82f9d2c57bdc9e102021-07-02T05:38:52ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852016-07-01147e100251110.1371/journal.pbio.1002511Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome.Michal CagalinecMailis LiivZuzana HodurovaMiriam Ann HickeyAnnika VaarmannMerle MandelAkbar ZebVinay ChoubeyMalle KuumDzhamilja SafiulinaEero VasarVladimir VekslerAllen KaasikDeficiency 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.http://europepmc.org/articles/PMC4951053?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michal Cagalinec Mailis Liiv Zuzana Hodurova Miriam Ann Hickey Annika Vaarmann Merle Mandel Akbar Zeb Vinay Choubey Malle Kuum Dzhamilja Safiulina Eero Vasar Vladimir Veksler Allen Kaasik |
spellingShingle |
Michal Cagalinec Mailis Liiv Zuzana Hodurova Miriam Ann Hickey Annika Vaarmann Merle Mandel Akbar Zeb Vinay Choubey Malle Kuum Dzhamilja Safiulina Eero Vasar Vladimir Veksler Allen Kaasik Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. PLoS Biology |
author_facet |
Michal Cagalinec Mailis Liiv Zuzana Hodurova Miriam Ann Hickey Annika Vaarmann Merle Mandel Akbar Zeb Vinay Choubey Malle Kuum Dzhamilja Safiulina Eero Vasar Vladimir Veksler Allen Kaasik |
author_sort |
Michal Cagalinec |
title |
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. |
title_short |
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. |
title_full |
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. |
title_fullStr |
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. |
title_full_unstemmed |
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. |
title_sort |
role of mitochondrial dynamics in neuronal development: mechanism for wolfram syndrome. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2016-07-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4951053?pdf=render |
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