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

Autor:	Marković A; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.; Faculty of Science, Charles University, 128 00 Prague, Czech Republic., Tauchmannová K; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Šimáková M; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Mlejnek P; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Kaplanová V; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Pecina P; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Pecinová A; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Papoušek F; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Liška F; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague, Czech Republic., Šilhavý J; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Mikešová J; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Neckář J; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Houštěk J; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic., Pravenec M; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague, Czech Republic., Mráček T; Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
Jazyk:	angličtina
Zdroj:	Biomedicines [Biomedicines] 2022 Jan 26; Vol. 10 (2). Date of Electronic Publication: 2022 Jan 26.
DOI:	10.3390/biomedicines10020276
Abstrakt:	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- Tmem70 ko / ko ), which leads to embryonic lethality. We generated SHR- Tmem70 ko / ko knockout rats expressing the Tmem70 wild-type transgene (SHR- Tmem70 ko / 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- Tmem70 ko / 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- Tmem70 ko / 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.
Databáze:	MEDLINE
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