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Article

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

1
Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
2
Faculty of Science, Charles University, 128 00 Prague, Czech Republic
3
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague, Czech Republic
*
Authors to whom correspondence should be addressed.
Present address: Institute of Organic Chemistry and Biochemistry of the CAS, 166 10 Prague, Czech Republic.
Academic Editors: Daniel L. Galvan and Alessandro Rimessi
Biomedicines 2022, 10(2), 276; https://doi.org/10.3390/biomedicines10020276
Received: 2 December 2021 / Revised: 5 January 2022 / Accepted: 18 January 2022 / Published: 26 January 2022
(This article belongs to the Special Issue Mitochondrial Dysfunction in Disease)
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. View Full-Text
Keywords: mitochondria disease; ATP synthase deficiency; TMEM70 factor; transgenic rescue; gene therapy mitochondria disease; ATP synthase deficiency; TMEM70 factor; transgenic rescue; gene therapy
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MDPI and ACS Style

Marković, A.; Tauchmannová, K.; Šimáková, M.; Mlejnek, P.; Kaplanová, V.; Pecina, P.; Pecinová, A.; Papoušek, F.; Liška, F.; Šilhavý, J.; Mikešová, J.; Neckář, J.; Houštěk, J.; Pravenec, M.; Mráček, T. Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat. Biomedicines 2022, 10, 276. https://doi.org/10.3390/biomedicines10020276

AMA Style

Marković A, Tauchmannová K, Šimáková M, Mlejnek P, Kaplanová V, Pecina P, Pecinová A, Papoušek F, Liška F, Šilhavý J, Mikešová J, Neckář J, Houštěk J, Pravenec M, Mráček T. Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat. Biomedicines. 2022; 10(2):276. https://doi.org/10.3390/biomedicines10020276

Chicago/Turabian Style

Marković, Aleksandra, Kateřina Tauchmannová, Miroslava Šimáková, Petr Mlejnek, Vilma Kaplanová, Petr Pecina, Alena Pecinová, František Papoušek, František Liška, Jan Šilhavý, Jana Mikešová, Jan Neckář, Josef Houštěk, Michal Pravenec, and Tomáš Mráček. 2022. "Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat" Biomedicines 10, no. 2: 276. https://doi.org/10.3390/biomedicines10020276

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