Effects of Tributyltin Chloride on Cybrids with or without an ATP Synthase Pathologic Mutation

Abstract

Background: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.Objectives: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.Methods: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.Results: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.Conclusions:In addition to the known genetic causes, our findings suggest that environmental exposure to TBTC might contribute to the etiology of striatal necrosis syndromes.Citation: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

Food derived respiratory complex I inhibitors modify the effect of Leber hereditary optic neuropathy mutations

“…The AmpFLSTR ® Identifiler ® PCR Amplification Kit (Life Technologies) was used to determine the cybrids nDNA genetic fingerprints. The molecular cytogenetic analysis was done according to already published procedures (Lopez-Gallardo et al, 2016).…”

“…We have previously suggested that mtDNA genetic background in the cytochrome b gene might affect the interaction with pesticides or pharmaceutical drugs (Gomez-Duran et al, 2011). Moreover, we found that mtDNA genetic variation modifies the off-target effects of ribosomal antibiotics used to fight pathogenic bacteria (Pacheu-Grau et al, 2013), and that the widely distributed pollutant tributyltin chloride, an ATP synthase inhibitor, modified the phenotypic effects caused by a pathological mtDNA mutation (Lopez-Gallardo et al, 2016). Thus, considering the interaction between mtDNA and environment factors is going to be important to explain the pathogenicity of mitochondrial disease due to mtDNA mutations.…”

The aetiology of cardiovascular disease: a role for mitochondrial DNA?

“…Another possibility is that the effect of an accumulation of mildly deleterious variants may only become clinically significant once a population is challenged by a rapid change of confounding factors, such as diet or other environmental factors (toxins). 126 , 127 …”