PUBLICATION

Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish

Authors: Sokol, A.M., Uszczynska-Ratajczak, B., Collins, M.M., Bazala, M., Topf, U., Lundegaard, P.R., Sugunan, S., Guenther, S., Kuenne, C., Graumann, J., Chan, S.S.L., Stainier, D.Y.R., Chacinska, A.
ID: ZDB-PUB-181127-22
Date: 2018
Source: PLoS Genetics 14: e1007743 (Journal)
Registered Authors: Chacinska, Agnieszka, Chan, Sherine, Lundegaard, Pia Rengtved, Stainier, Didier
Keywords: none
Datasets: GEO:GSE113272
MeSH Terms: none
PubMed: 30457989 Full text @ PLoS Genet.

Abstract

Development and function of tissues and organs are powered by the activity of mitochondria. In humans, inherited genetic mutations that lead to progressive mitochondrial pathology often manifest during infancy and can lead to death, reflecting the indispensable nature of mitochondrial biogenesis and function. Here, we describe a zebrafish mutant for the gene mia40a (chchd4a), the life-essential homologue of the evolutionarily conserved Mia40 oxidoreductase which drives the biogenesis of cysteine-rich mitochondrial proteins. We report that mia40a mutant animals undergo progressive cellular respiration defects and develop enlarged mitochondria in skeletal muscles before their ultimate death at the larval stage. We generated a deep transcriptomic and proteomic resource that allowed us to identify abnormalities in the development and physiology of endodermal organs, in particular the liver and pancreas. We identify the acinar cells of the exocrine pancreas to be severely affected by mutations in the MIA pathway. Our data contribute to a better understanding of the molecular, cellular and organismal effects of mitochondrial deficiency, important for the accurate diagnosis and future treatment strategies of mitochondrial diseases.

Errata / Notes

Corrected by ZDB-PUB-190201-9

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	aerobic respiration process quality, abnormal	Fig. 4
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	liver cp expression decreased amount, abnormal	Fig. 6
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	liver rbp2b expression decreased amount, abnormal	Fig. 6
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	pancreas decreased size, abnormal	Fig. 6
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	skeletal muscle mitochondrion has extra parts of type skeletal muscle inclusion body, abnormal	Fig. 3
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	skeletal muscle mitochondrion morphology, abnormal	Fig. 3
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	whole organism Ab1-cox4i1 labeling decreased amount, abnormal	Fig. S4
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	whole organism Ab1-ndufa9 labeling decreased amount, abnormal	Fig. S4
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	whole organism glucose decreased amount, abnormal	Fig. 4
chchd4a^{bns292/bns292} (AB)	standard conditions	Day 5	whole organism lactate increased amount, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
bns292		Small Deletion	chchd4a
bns293		Small Deletion	chchd4b
cms1Tg	Tg(Xla.Eef1a1:mlsEGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
chchd4a	TALEN1-chchd4a	TALEN
chchd4b	TALEN1-chchd4b	TALEN

Fish

Fish
AB
chchd4a^{bns292/bns292} (AB)
chchd4a^{bns292/bns292}; cms1Tg
chchd4a^bns292/+ (AB)
chchd4a^bns292/+; cms1Tg
cms1Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Sokol et al., 2018 ZDB-PUB-181127-22 PMID:30457989

Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish

Sokol et al., 2018

ZDB-PUB-181127-22
PMID:30457989