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Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat

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    SYSNO ASEP0555857
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleGenetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat
    Author(s) Marković, Aleksandra (FGU-C) RID, ORCID
    Tauchmannová, Kateřina (FGU-C) RID, ORCID
    Šimáková, Miroslava (FGU-C) RID, ORCID
    Mlejnek, Petr (FGU-C) RID, ORCID
    Kaplanová, Vilma (FGU-C) RID
    Pecina, Petr (FGU-C) RID, ORCID
    Pecinová, Alena (FGU-C) RID, ORCID, SAI
    Papoušek, František (FGU-C)
    Liška, František (FGU-C) ORCID, RID
    Šilhavý, Jan (FGU-C) RID, ORCID
    Mikešová, Jana (FGU-C) RID, ORCID
    Neckář, Jan (FGU-C) RID, ORCID
    Houštěk, Josef (FGU-C) RID, ORCID
    Pravenec, Michal (FGU-C) RID, ORCID
    Mráček, Tomáš (FGU-C) RID, ORCID
    Article number276
    Source TitleBiomedicines. - : MDPI
    Roč. 10, č. 2 (2022)
    Number of pages22 s.
    Languageeng - English
    CountryCH - Switzerland
    Keywordsmitochondria disease ; ATP synthase deficiency ; TMEM70 factor ; transgenic rescue ; gene therapy
    OECD categoryBiochemistry and molecular biology
    R&D ProjectsGA20-25768S GA ČR - Czech Science Foundation (CSF)
    NU21-07-00550 GA MZd - Ministry of Health (MZ)
    Method of publishingOpen access
    Institutional supportFGU-C - RVO:67985823
    UT WOS000763908900001
    EID SCOPUS85124327235
    AnnotationMutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16–49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.
    WorkplaceInstitute of Physiology
    ContactLucie Trajhanová,, Tel.: 241 062 400
    Year of Publishing2023
    Electronic address
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