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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
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevGenetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat
    Tvůrce(i) 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
    Číslo článku276
    Zdroj.dok.Biomedicines. - : MDPI
    Roč. 10, č. 2 (2022)
    Poč.str.22 s.
    Jazyk dok.eng - angličtina
    Země vyd.CH - Švýcarsko
    Klíč. slovamitochondria disease ; ATP synthase deficiency ; TMEM70 factor ; transgenic rescue ; gene therapy
    Obor OECDBiochemistry and molecular biology
    CEPGA20-25768S GA ČR - Grantová agentura ČR
    NU21-07-00550 GA MZd - Ministerstvo zdravotnictví
    Způsob publikováníOpen access
    Institucionální podporaFGU-C - RVO:67985823
    UT WOS000763908900001
    EID SCOPUS85124327235
    DOI10.3390/biomedicines10020276
    AnotaceMutations 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.
    PracovištěFyziologický ústav
    KontaktLucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
    Rok sběru2023
    Elektronická adresahttps://www.mdpi.com/2227-9059/10/2/276
Počet záznamů: 1