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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F16%3A00471806" target="_blank" >RIV/68378050:_____/16:00471806 - isvavai.cz</a>

Alternative codes found

RIV/67985823:_____/16:00471806 RIV/00216208:11110/16:10358960

Result on the web

<a href="http://dx.doi.org/10.1093/hmg/ddw295" target="_blank" >http://dx.doi.org/10.1093/hmg/ddw295</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/hmg/ddw295" target="_blank" >10.1093/hmg/ddw295</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Human Molecular Genetics

ISSN

0964-6906

e-ISSN

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Volume of the periodical

25

Issue of the periodical within the volume

21

Country of publishing house

GB - UNITED KINGDOM

Number of pages

12

Pages from-to

4674-4685

UT code for WoS article

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EID of the result in the Scopus database

2-s2.0-85014822460