TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis

Abstract

Mammalian complex V (F1F0-ATP synthase or ATPase) uses the proton gradient to generate ATP during oxidative phosphorylation and requires several helper proteins, including TMEM70, to form the holoenzyme in a stepwise process in which nuclear DNA is combined with mitochondrial DNA-encoded subunits. We report the clinical and molecular findings in three patients presenting lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic cardiomyopathy. All three showed an isolated defect of fully assembled ATP synthase in association with a "common" (c.317-2A > G) and a new (c.628A > C/p.T210P) variant in TMEM70. Interestingly, one of the patients also showed nitric oxide-responsive pulmonary arterial hypertension, a finding never before associated with TMEM70 deficiency. In addition to widening the clinical and mutational spectrum of defective ATP synthase, our study also suggests that mutant TMEM70 associates in high molecular weight complexes (470-550 kDa) when expressed in Hela cells and exerts a direct action in ATP synthase biogenesis and assembly, mediating the incorporation of F1 moieties.

TMEM70 deficiency: long‐term outcome of 48 patients

“…After removal of its 9 kDa Nterminal mitochondrial targeting signal sequence, it is processed to a 21 kDa mature protein and imported into the inner mitochondrial membrane (Calvo et al 2006;He jz la ro váetal 2011). TMEM70 is an important factor for the biogenesis and stabilisation of ATP synthase, but its exact role still needs to be determined (Torraco et al 2012;Hejzlarová et al 2011). Recently, the protein structure has been demonstrated (Kratochvílová et al 2014).…”

Mitochondrial complex deficiency by novel compound heterozygous TMEM70 variants and correlation with developmental delay, undescended testicle, and left ventricular noncompaction in a Japanese patient: A case report

“…TMEM70 is an essential factor in the biogenesis and stabilization of ATP synthase . The mammalian OXPHOS comprises five multi‐subunit complexes, three of which, complexes I, III, and IV, support in the generation of a proton gradient across the inner mitochondrial membrane.…”

“…TMEM70 is an essential factor in the biogenesis and stabilization of ATP synthase. 10,11 The mammalian OXPHOS comprises five multi-subunit complexes, three of which, complexes I, III, and IV, support in the generation of a proton gradient across the inner mitochondrial membrane. Complex V, also named ATP synthase, transfers protons back to the inner mitochondrial membrane for the conversion of ADP and inorganic phosphate to ATP.…”

Mitochondrial Diseases Part I: Mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors

“…A distinct group of inherited inborn defects of ATP synthase is due to mutations in nuclear genes that give rise to a typical phenotype characterized by 3-methylglutaconic aciduria, hypertrophic cardiomyopathy, neonatal-onset hypotonia and lactic acidosis. Only one nuclear encoded structural subunit (ATP5E) has been found mutated in patients (Mayr, 2010), while the most of nuclear defects affect assembly factors of complex V as ATP12 (De Meirleir, 2004) and TMEM70 (Cizkova, 2008; Torraco, 2012). In particular, TMEM70 is so far considered the most common cause of mendelian-inherited isolated ATP synthase deficiency (Spiegel, 2011).…”

“…A good candidate would be the TMEM70 gene since a growing number of patients with ATP synthase deficiencies have mutations mostly in this gene (Torraco, 2012). A CV deficient mouse will be indispensable to characterize the mechanism of pathogenesis and test compounds that have already given promising results in both yeast and cybrid cell lines (Couplan, 2011).…”