PUBLICATION
Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response
- Authors
- Légaré, V.P., Rampal, C.J., Gurberg, T.J.N., Aaltonen, M.J., Janer, A., Zinman, L., Shoubridge, E.A., Armstrong, G.A.B.
- ID
- ZDB-PUB-230218-30
- Date
- 2023
- Source
- Developmental Neurobiology 83(1-2): 54-69 (Journal)
- Registered Authors
- Armstrong, Gary A.B.
- Keywords
- CHCHD10, CHCHD2, amyotrophic lateral sclerosis, mitochondria, zebrafish
- MeSH Terms
-
- Animals
- DNA-Binding Proteins/genetics
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism
- Mutation
- Phenotype
- Transcription Factors*/genetics
- Transcription Factors*/metabolism
- Zebrafish/metabolism
- PubMed
- 36799027 Full text @ Dev. Neurobiol.
Citation
Légaré, V.P., Rampal, C.J., Gurberg, T.J.N., Aaltonen, M.J., Janer, A., Zinman, L., Shoubridge, E.A., Armstrong, G.A.B. (2023) Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response. Developmental Neurobiology. 83(1-2):54-69.
Abstract
Mutations in CHCHD10 and CHCHD2, encoding two paralogous mitochondrial proteins, have been identified in cases of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and Parkinson's disease (PD). Their role in disease is unclear, though both have been linked to mitochondrial respiration and mitochondrial stress responses. Here we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to motor impairment, reduced survival and compromised neuromuscular junction (NMJ) integrity in larval zebrafish. Compensation by Chchd10 was observed in the chchd2-/- model, but not by Chchd2 in the chchd10 -/- model. The assembly of mitochondrial respiratory chain Complex I was impaired in chchd10 -/- and chchd2 -/- zebrafish larvae, but unexpectedly not in a double chchd10 -/- & chchd2 -/- model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. We observed transcriptional activation markers of the mitochondrial integrated stress response (mt-ISR) in the double chchd10 -/- and chchd2 -/- KO model, suggesting that this pathway is involved in the restoration of Complex I assembly in our double KO model. The data presented here, demonstrates that the Complex I assembly defect in our single KO models arises independently of the mt-ISR. Furthermore, this study provides evidence that both proteins are required for normal vertebrate development. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping