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Updated: Mar 22, 2026
An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
Effects of Tributyltin Chloride on Cybrids with or without an ATP Synthase Pathologic Mutation
Ester López-Gallardo1, Laura Llobet, Sonia Emperador
1Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
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.
Insights
Environmental toxin tributyltin chloride (TBTC) can mimic mitochondrial DNA (mtDNA) mutations causing striatal necrosis. TBTC exposure may contribute to these rare OXPHOS disorders, alongside genetic factors.
Area of Science:
- Mitochondrial biology and genetics
- Environmental toxicology
- Human health and disease
Background:
- Oxidative phosphorylation (OXPHOS) disorders, including striatal necrosis syndromes, are often caused by genetic mutations in nuclear or mitochondrial DNA (mtDNA).
- However, some OXPHOS disorders remain unexplained by genetic mutations, suggesting potential roles for environmental factors.
- Environmental toxins can mimic biochemical effects of mutations or modify their expression.
Purpose of the Study:
- To investigate the interaction between the mitochondrial ATP synthase 6 (MT-ATP6) subunit and environmental exposures.
- To understand how environmental factors contribute to phenotypic differences in mitochondriopathies like striatal necrosis.
Main Methods:
- Analysis of transmitochondrial cell lines with and without an ATP synthase mutation.
- Exposure of these cell lines to tributyltin chloride (TBTC), an environmental ATP synthase inhibitor, at concentrations found in human blood.
- Assessment of bioenergetics and phenotypic effects.
Main Results:
- Tributyltin chloride (TBTC) altered the phenotypic effects of a pathological mtDNA mutation in ATP synthase.
- Wild-type cells exposed to TBTC exhibited similar bioenergetic profiles to untreated cells with the mutation.
- This indicates TBTC can induce OXPHOS dysfunction mimicking genetic defects.
Conclusions:
- Environmental exposure to TBTC may be an etiologic factor in striatal necrosis syndromes.
- Findings suggest that environmental toxins, in addition to genetic mutations, contribute to OXPHOS disorders.
- This highlights the importance of considering environmental exposures in diagnosing and understanding mitochondriopathies.
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