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

Kód výsledku v 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>

Nalezeny alternativní kódy

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

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

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

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Human Molecular Genetics

ISSN

0964-6906

e-ISSN

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Svazek periodika

25

Číslo periodika v rámci svazku

21

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

12

Strana od-do

4674-4685

Kód UT WoS článku

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EID výsledku v databázi Scopus

2-s2.0-85014822460