Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

Nicola Baker, Graham Hamilton, Jonathan M. Wilkes, Sebastian Hutchinson, Michael P. Barrett, David Horn (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    25 Citations (Scopus)

    Abstract

    Anti-trypanosomal drugs, used to tackle lethal human and animal diseases, target an unusual parasite DNA structure in a cellular compartment known as the mitochondrion. Using a high-throughput genetic approach to study drug resistance, we identified every component of a molecular rotor that couples ATP hydrolysis to proton transport across non-mitochondrial membranes. Surprisingly, this molecular machine was found to communicate with a related mitochondrial rotor and, when defective, rendered the mitochondrial DNA structure obsolete. Our findings reveal new potential mechanisms of multidrug resistance in trypanosomes. They also suggest that communication between these rotors in two separate cellular compartments could be conserved through evolution, reflecting an unanticipated and important aspect of environmental sensing and metabolic control in nucleated cells.

    Original languageEnglish
    Pages (from-to)9112-9117
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume112
    Issue number29
    DOIs
    Publication statusPublished - 21 Jul 2015

    Keywords

    • Brucei
    • Mitochondrion
    • Nagana
    • Petite
    • Samorin

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