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Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice

SYSNO ASEP	0471806
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice
Author(s)	Vrbacký, Marek (FGU-C)_{RID, ORCID} Kovalčíková, Jana (FGU-C) Chawengsaksophak, Kallayanee (UMG-J)_ORCID Beck, Inken (UMG-J)_RID Mráček, Tomáš (FGU-C)_{RID, ORCID} Nůsková, Hana (FGU-C)_{RID, ORCID} Sedmera, David (FGU-C)_{RID, ORCID, SAI} Papoušek, František (FGU-C) Kolář, František (FGU-C)_{RID, ORCID, SAI} Sobol, Margaryta (UMG-J)_RID Hozák, Pavel (UMG-J)_{RID, ORCID} Sedláček, Radislav (UMG-J)_RID Houštěk, Josef (FGU-C)_{RID, ORCID}
Source Title	Human Molecular Genetics. - : Oxford University Press - ISSN 0964-6906 Roč. 25, č. 21 (2016), s. 4674-4685
Number of pages	12 s.
Language	eng - English
Country	GB - United Kingdom
Keywords	mouse knockout ; mitochondria ; ATP synthase ; TMEM70 ; biogenesis ; mitochondrial diseases
Subject RIV	EB - Genetics ; Molecular Biology
OECD category	Human genetics
R&D Projects	GB14-36804G GA ČR - Czech Science Foundation (CSF)
	LL1204 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	TE01020118 GA TA ČR - Technology Agency of the Czech Republic (TA ČR)
	LM2015062 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	NV16-33018A GA MZd - Ministry of Health (MZ)
	LM2015040 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	FGU-C - RVO:67985823 ; UMG-J - RVO:68378050
UT WOS	000397061300006
EID SCOPUS	85014822460
DOI	10.1093/hmg/ddw295
Annotation	TMEM70, a 21 kDa protein localized in the inner mitochondrial membrane, has been shown to facilitate the biogenesis of mammalian F1Fo ATP synthase. Mutations of the TMEM70 gene represent the most frequent cause of isolated ATP synthase deficiency resulting in a severe mitochondrial disease presenting as neonatal encephalo-cardiomyopathy (OMIM 604273). To better understand the biological role of this factor, we generated Tmem70 deficient mice and found that the homozygous Tmem70 -/- knockouts exhibited profound growth retardation and embryonic lethality at approximately 9.5 days post coitum. Blue-Native electrophoresis demonstrated an isolated deficiency in fully assembled ATP synthase in the Tmem70 -/- embryos (80% decrease) and a marked accumulation of F1 complexes indicative of impairment in ATP synthase biogenesis that was stalled at the early stage, following the formation of F1 oligomer. Consequently, a decrease in ADP-stimulated State 3 respiration, respiratory control ratio and ATP/ADP ratios, indicated compromised mitochondrial ATP production. In Tmem70 -/- embryos development of the cardiovascular system was delayed and heart mitochondrial ultrastructure disturbed, with concentric or irregular cristae structures. Tmem70 +/- heterozygous mice were fully viable and displayed normal postnatal growth and development of the mitochondrial oxidative phosphorylation system. Nevertheless, they presented with mild deterioration of heart function. Our results demonstrated that Tmem70 knockout in the mouse results in embryonic lethality due to the lack of ATP synthase and impairment of mitochondrial energy provision. This is analogous to TMEM70 dysfunction in humans and verifies the crucial role of this factor in the biosynthesis and assembly of mammalian ATP synthase.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2017

Number of the records: 1