PUBLICATION

The zebrafish orthologue of the human hepatocerebral disease gene MPV17 plays pleiotropic roles in mitochondria

Authors

Martorano, L., Peron, M., Laquatra, C., Lidron, E., Facchinello, N., Meneghetti, G., Tiso, N., Rasola, A., Ghezzi, D., Argenton, F.

ID

ZDB-PUB-190306-3

Date

2019

Source

Disease models & mechanisms 12(3): (Journal)

Registered Authors

Argenton, Francesco, Facchinello, Nicola, Tiso, Natascia

Keywords

Dehydroorotate dehydrogenase, Iridophores, Mitochondrial DNA depletion syndrome, Pyrimidine, Vitamin b13

MeSH Terms

Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Animals
Mitochondrial Proteins/chemistry*
Mitochondrial Proteins/genetics
Mitochondrial Proteins/metabolism*
Humans
Genetic Pleiotropy*
Pyrimidines/biosynthesis
Zebrafish/genetics
Zebrafish/metabolism*
Liver/metabolism
Nucleotides/metabolism
Membrane Proteins/chemistry*
Membrane Proteins/genetics
Membrane Proteins/metabolism*
Mutation/genetics
Phenotype
DNA, Mitochondrial/genetics
Mitochondria/metabolism*
Mitochondria/ultrastructure
Stress, Physiological
Electron Transport
Larva/genetics
Larva/metabolism
Sequence Homology, Amino Acid*
Mitochondrial Diseases/metabolism*
Gene Dosage
Biosynthetic Pathways

(all 29)

PubMed

30833296 Full text @ Dis. Model. Mech.

Abstract

Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction of mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17, a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. Zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In our work, we have characterized the mitochondrial phenotype of mpv17^-/- larvae and found early and severe ultrastructural alterations in liver mitochondria as well as a significant impairment of the respiratory chain leading to activation of the mitochondrial quality control. Our results provide evidences for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality while its effect on mtDNA copy number seems to be subordinate. Considering that a role in nucleotides availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17^-/- KO and that mpv17^-/- KO have an impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). The treatment with OA, an easily available food supplement, significantly increased both iridophores number and mtDNA content of mpv17^-/- mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17-related MDS.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
mpv17l	mpv17^a9/a9	standard conditions	Day 6	whole organism	RTPCR	Fig. 1
mpv17l	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 1
mpv17l2	mpv17^a9/a9	standard conditions	Protruding-mouth	anatomical structure	ISH	Fig. S1
mpv17l2	WT	standard conditions	Protruding-mouth	anatomical structure	ISH	Fig. S1
mt-cyb	mpv17^a9/a9	standard conditions	Day 6	whole organism	RTPCR	Fig. 3
mt-cyb	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 3
uqcrc1	mpv17^a9/a9	standard conditions	Day 6	whole organism	RTPCR	Fig. 3
uqcrc1	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 3

1 - 8 of 8

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: leflunomide	Protruding-mouth	post-vent region has fewer parts of type iridophore, abnormal	Fig. 5
WT	chemical treatment: leflunomide	Adult	liver dihydroorotase activity decreased efficacy, abnormal	Fig. 6
mpv17^a9/a9	control	Protruding-mouth	post-vent region has fewer parts of type iridophore, abnormal	Fig. 6
mpv17^a9/a9	control	Protruding-mouth	post-vent region has fewer parts of type iridophore, abnormal	Fig. 5
mpv17^a9/a9	control	Protruding-mouth	whole organism mitochondrial chromosome decreased amount, abnormal	Fig. 6
mpv17^a9/a9	standard conditions	Protruding-mouth	post-vent region has fewer parts of type iridophore, abnormal	Fig. S4
mpv17^a9/a9	standard conditions	Day 4	aerobic respiration decreased occurrence, abnormal	Fig. 3
mpv17^a9/a9	standard conditions	Day 4	oxidative phosphorylation decreased occurrence, abnormal	Fig. 3
mpv17^a9/a9	standard conditions	Day 4	whole organism respiratory chain complex decreased amount, abnormal	Fig. 3
mpv17^a9/a9	standard conditions	Day 6	liver mitochondrial crista absent, abnormal	Fig. 2

1 - 10 of 25

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
a9		Complex	mpv17
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion
ia301Tg	Tg(Hsa.Cox8a:MLS-EGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
mitochondrial DNA depletion syndrome	mpv17^a9/a9	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
gz15Tg; ia301Tg
mpv17^a9/a9
mpv17^a9/a9; gz15Tg; ia301Tg
WT

Antibodies

Name	Type	Isotypes	Host Organism
Ab1-actb	monoclonal	IgG1	Mouse
Ab2-hspa9	polyclonal	IgG	Rabbit
Ab3-tomm20	polyclonal		Rabbit

Orthology

Gene	Orthology
mpv17

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP

Mapping

Martorano et al., 2019 ZDB-PUB-190306-3 PMID:30833296

The zebrafish orthologue of the human hepatocerebral disease gene MPV17 plays pleiotropic roles in mitochondria

Martorano et al., 2019

ZDB-PUB-190306-3
PMID:30833296