Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome

Overview

Journal PLoS Biol

Specialty Biology

Date 2016 Jul 20

PMID 27434582

Citations 75

Authors

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

Affiliations

Soon will be listed here.

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.

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