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

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    0555857 - FGÚ 2023 RIV CH eng J - Článek v odborném periodiku
    Marković, Aleksandra - Tauchmannová, Kateřina - Šimáková, Miroslava - Mlejnek, Petr - Kaplanová, Vilma - Pecina, Petr - Pecinová, Alena - Papoušek, František - Liška, František - Šilhavý, Jan - Mikešová, Jana - Neckář, Jan - Houštěk, Josef - Pravenec, Michal - Mráček, Tomáš
    Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat.
    Biomedicines. Roč. 10, č. 2 (2022), č. článku 276. E-ISSN 2227-9059
    Grant CEP: GA ČR(CZ) GA20-25768S; GA MZd(CZ) NU21-07-00550
    Grant ostatní: AV ČR(CZ) AP1502
    Program: Akademická prémie - Praemium Academiae
    Institucionální podpora: RVO:67985823
    Klíčová slova: mitochondria disease * ATP synthase deficiency * TMEM70 factor * transgenic rescue * gene therapy
    Obor OECD: Biochemistry and molecular biology
    Impakt faktor: 4.757, rok: 2021
    Způsob publikování: Open access
    https://www.mdpi.com/2227-9059/10/2/276

    Mutations 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.
    Trvalý link: http://hdl.handle.net/11104/0330319

     
     
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