title: 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.
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Meschini
authors.forename: Martha Elisa
authors.initials: ME
authors.lastname: Vazquez-Memije
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.forename: Marzia
authors.initials: M
authors.lastname: Bianchi
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000096:biosynthesis*; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics; D007223:Infant; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency*; D008969:Molecular Sequence Data; D009154:Mutation; D017422:Sequence Analysis, DNA; D012867:Skin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C533106:TMEM70 protein, human; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein