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).