title: Effects of Tributyltin Chloride on Cybrids with or without an ATP Synthase Pathologic Mutation.
abstract: The oxidative phosphorylation system (OXPHOS) includes nuclear chromosome (nDNA)- and mitochondrial DNA (mtDNA)-encoded polypeptides. Many rare OXPHOS disorders, such as striatal necrosis syndromes, are caused by genetic mutations. Despite important advances in sequencing procedures, causative mutations remain undetected in some patients. It is possible that etiologic factors, such as environmental toxins, are the cause of these cases. Indeed, the inhibition of a particular enzyme by a poison could imitate the biochemical effects of pathological mutations in that enzyme. Moreover, environmental factors can modify the penetrance or expressivity of pathological mutations.
  
  
  
  We studied the interaction between mitochondrially encoded ATP synthase 6 (p.MT-ATP6) subunit and an environmental exposure that may contribute phenotypic differences between healthy individuals and patients suffering from striatal necrosis syndromes or other mitochondriopathies.
  
  
  
  We analyzed the effects of the ATP synthase inhibitor tributyltin chloride (TBTC), a widely distributed environmental factor that contaminates human food and water, on transmitochondrial cell lines with or without an ATP synthase mutation that causes striatal necrosis syndrome. Doses were selected based on TBTC concentrations previously reported in human whole blood samples.
  
  
  
  TBTC modified the phenotypic effects caused by a pathological mtDNA mutation. Interestingly, wild-type cells treated with this xenobiotic showed similar bioenergetics when compared with the untreated mutated cells.
  
  
  
  In addition to the known genetic causes, our findings suggest that environmental exposure to TBTC might contribute to the etiology of striatal necrosis syndromes.
  
  
  
  López-Gallardo E, Llobet L, Emperador S, Montoya J, Ruiz-Pesini E. 2016. Effects of tributyltin chloride on cybrids with or without an ATP synthase pathologic mutation. Environ Health Perspect 124:1399-1405; http://dx.doi.org/10.1289/EHP182.
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: López-Gallardo
authors.forename: Laura
authors.initials: L
authors.lastname: Llobet
authors.forename: Sonia
authors.initials: S
authors.lastname: Emperador
authors.forename: Julio
authors.initials: J
authors.lastname: Montoya
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruiz-Pesini
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009336:Necrosis / Q000235:genetics; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D004785:Environmental Pollutants; D014220:Trialkyltin Compounds; C011559:tributyltin; C412204:ATP synthase subunit 6; D025261:Mitochondrial Proton-Translocating ATPases