An Atypical Mitochondrial Carrier That Mediates Drug Action in

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Human and animal trypanosomiases caused by Trypanosoma brucei parasites represent major burdens to human welfare and agricultural development in rural sub-Saharan Africa. Although the numbers of infected humans have decreased continuously during the last decades, emerging resistance and adverse side effects against commonly used drugs require an urgent need for the identification of novel drug targets and the development of new drugs. Using an unbiased genome-wide screen to search for genes involved in the mode of action of trypanocidal compounds, we identified a member of the mitochondrial carrier family, TbMCP14, as prime candidate to mediate the action of a group of anti-parasitic choline analogs against T. brucei. Ablation of TbMCP14 expression by RNA interference or gene deletion decreases the susceptibility of parasites towards the compounds while over-expression of the carrier shows the opposite effect. In addition, down-regulation of TbMCP14 protects mitochondria from drug-induced decrease in mitochondrial membrane potential and reduces proline-dependent ATP production. Together, the results demonstrate that TbMCP14 is involved in energy production in T. brucei, possibly by acting as a mitochondrial proline carrier, and reveal TbMCP14 as candidate protein for drug action or targeting.

Vyšlo v časopise: An Atypical Mitochondrial Carrier That Mediates Drug Action in. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004875
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004875

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