Kovalcikova 2015 Abstract MiPschool London 2015

From Bioblast
TMEM70 ablation leads to embryonic lethality in mouse knockout due to impairment of ATP synthase.


Kovalcikova J, Vrbacky M, Nuskova H, Chawengsaksophak K, Beck I, Sedlacek R, Hozak P, Sedmera D, Houstek J (2015)

Event: MiPschool London 2015

TMEM70 is a transmembrane protein localized in the inner mitochondrial membrane and involved in the biogenesis of the eukaryotic ATP synthase. TMEM70 mutations cause isolated deficiency of ATP synthase often resulting in a fatal neonatal mitochondrial encephalocardiomyopathy, lactic acidosis and 3-methylglutaconic aciduria in patients.

To clarify the exact function of this factor, we generated Tmem70 knockout mice by embryonic stem cell technology. While the heterozygous mice were viable and developmentally normal, the homozygous embryos were distinctly growth retarded and died during the embryonic development about 9.5 days post coitum. Confocal microscopy revealed delayed development of the cardiovascular system and electron microscopy indicated disturbed mitochondrial morphology in the homozygous when compared to the wild type embryos. Blue native electrophoresis demonstrated isolated defect of ATP synthase in the homozygous embryos with the content of fully assembled F1Fo ATP synthase decreased to less than 20% of wild types. Moreover, targeted metabolomic analysis showed increase of 3-methylglutaconate and depletion of energetic intermediates in the homozygous embryos compared to the heterozygotes and wild types. In contrast, comparison of the viable heterozygous and wild type mice aged 5 and 14 weeks did not show any significant differences in the heart and liver content of respiratory chain complexes, oxygen consumption, ATP synthase assembly and ATPase hydrolytic activity.

In conclusion, this first direct demonstration of the biological role of TMEM70 in experimental animals shows that Tmem70 deficiency in the mouse has lethal consequences that are analogous to TMEM70 dysfunction in humans.

β€’ O2k-Network Lab: CZ Prague Houstek J, CZ Prague Kalous M

Labels: MiParea: Developmental biology, Patients  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart, Liver 

Regulation: ATP production 


1-Dept Bioenergetics, Inst Physiol Czech Acad Sci. - [email protected]

2-Inst Mol Genet Czech Acad Sci

3-Dept Cardiovascular Morphogenesis, Inst Physiol Czech Acad Sci, Prague, Czech Republic


Supported by the Grant Agency of the Czech Republic (P303/11/0970, 14-36804G) and Grant Agency of the Charles Uni (726214).

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