TCDB is operated by the Saier Lab Bioinformatics Group

8.A.96.  The TMEM70 (TMEM70) Family 

Patients with nuclear genetic defects of mitochondrial ATP synthase are characterized by early onset, lactic acidosis, 3-methylglutaconic aciduria, hypertrophic cardiomyopathy and encephalopathy, and most cases have a fatal outcome. Patient tissues show isolated defects of the ATP synthase complex, and its content decreases to ~ 30% of normal due to altered enzyme biosynthesis and assembly. A mutations in the TMEM70 gene encoding a 30kD mitochondrial protein is the cause of the disease. An altered synthesis of this factor in ATP synthase biogenesis was found in most of the known patients with decreased ATP synthase content (Houstek et al. 2009). TMEM70 is specific to higher eukaryotes.  Upregluation of respiratory complexes III and IV results from these mutations in TMEM70 (Havlíčková Karbanová et al. 2012).  Mitochondrial diseases with cardiomyopathies such as the ones caused by TMEM70 mutations have been reviewed (El-Hattab and Scaglia 2016). TMEM70 downregulation promotes the Warburg effect, which directs tumor progression,  hepatocarcinogenesis, in rats (Mizukami et al. 2017). TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme, and TMEM70 absence causes severe ATP-synthase deficiency and leads to a neonatal mitochondrial encephalocardiomyopathy in humans (Kovalčíková et al. 2019). The role of TMEM70 is thus to increase the low efficacy of spontaneous assembly of the subunit c oligomer, the rate-limiting step in ATP-synthase biogenesis. Thus, TMEM70 forms oligomeric scaffolds within mitochondrial cristae, promoting in situ assembly of mammalian ATP synthase proton channels (Bahri et al. 2020).

References associated with 8.A.96 family:

Bahri, H., J. Buratto, M. Rojo, J.P. Dompierre, B. Salin, C. Blancard, S. Cuvellier, M. Rose, A.B.A. Elgaaied, E. Tetaud, J.P. di Rago, A. Devin, and S. Duvezin-Caubet. (2020). TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel. Biochim. Biophys. Acta. Mol. Cell Res 118942. [Epub: Ahead of Print] 33359711
El-Hattab, A.W. and F. Scaglia. (2016). Mitochondrial Cardiomyopathies. Front Cardiovasc Med 3: 25. 27504452
Havlíčková Karbanová, V., A. Cížková Vrbacká, K. Hejzlarová, H. Nůsková, V. Stránecký, A. Potocká, S. Kmoch, and J. Houštěk. (2012). Compensatory upregulation of respiratory chain complexes III and IV in isolated deficiency of ATP synthase due to TMEM70 mutation. Biochim. Biophys. Acta. 1817: 1037-1043. 22433607
He, S., G. Tan, Q. Liu, K. Huang, J. Ren, X. Zhang, X. Yu, P. Huang, and C. An. (2011). The LSD1-interacting protein GILP is a LITAF domain protein that negatively regulates hypersensitive cell death in Arabidopsis. PLoS One 6: e18750. 21526181
Houstek, J., S. Kmoch, and J. Zeman. (2009). TMEM70 protein - a novel ancillary factor of mammalian ATP synthase. Biochim. Biophys. Acta. 1787: 529-532. 19103153
Kovalčíková, J., M. Vrbacký, P. Pecina, K. Tauchmannová, H. Nůsková, V. Kaplanová, A. Brázdová, L. Alán, J. Eliáš, K. Čunátová, V. Kořínek, R. Sedlacek, T. Mráček, and J. Houštěk. (2019). TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme. FASEB J. fj201900685RR. [Epub: Ahead of Print] 31652072
Mizukami, S., Y. Watanabe, K. Nakajima, Y. Hasegawa-Baba, M. Jin, T. Yoshida, and M. Shibutani. (2017). Downregulation of TMEM70 in Rat Liver Cells After Hepatocarcinogen Treatment Related to the Warburg Effect in Hepatocarcinogenesis Producing GST-P-Expressing Proliferative Lesions. Toxicol Sci 159: 211-223. 28903497