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

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

doi:https://dx.doi.org/10.3390/biomedicines10020276

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

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SYSNO ASEP	0555857
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Genetic 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, ORCID} 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 number	276
Source Title	Biomedicines. - : MDPI Roč. 10, č. 2 (2022)
Number of pages	22 s.
Language	eng - English
Country	CH - Switzerland
Keywords	mitochondria disease ; ATP synthase deficiency ; TMEM70 factor ; transgenic rescue ; gene therapy
OECD category	Biochemistry and molecular biology
R&D Projects	GA20-25768S GA ČR - Czech Science Foundation (CSF)
	NU21-07-00550 GA MZd - Ministry of Health (MZ)
Method of publishing	Open access
Institutional support	FGU-C - RVO:67985823
UT WOS	000763908900001
EID SCOPUS	85124327235
DOI	https://doi.org/10.3390/biomedicines10020276
Annotation	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.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2023
Electronic address	https://www.mdpi.com/2227-9059/10/2/276

Number of the records: 1