Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-09, Vol.110 (36), p.14741-14746
• Main Authors: Dean, Samuel, Gould, Matthew K., Dewar, Caroline E., Schnaufer, Achim C.
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Adenosine triphosphatases; Amino Acid Sequence; Animals; Biological Sciences; Biosynthesis; Blotting, Western; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - pharmacology; Cell growth; Cell lines; DNA, Kinetoplast - genetics; DNA, Kinetoplast - metabolism; Flow Cytometry; Gene expression; Genetic mutation; Genome, Mitochondrial - genetics; Genomics; Glossina; Humans; Insects; Kinetoplast DNA; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - genetics; Membrane Potential, Mitochondrial - physiology; Mitochondrial DNA; Mitochondrial Proton-Translocating ATPases - chemistry; Mitochondrial Proton-Translocating ATPases - genetics; Mitochondrial Proton-Translocating ATPases - metabolism; Models, Molecular; Molecular Sequence Data; Mutation; Parasites; Parasitism; Point Mutation; Protein Conformation; Protein Subunits - chemistry; Protein Subunits - genetics; Protein Subunits - metabolism; Proton Ionophores - pharmacology; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Sequence Homology, Amino Acid; Trypanosoma - genetics; Trypanosoma - metabolism; Trypanosoma brucei; Trypanosome; Tsetse Flies - parasitology; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1305404110

Viability of the tsetse fly-transmitted African trypanosome Trypanosoma brucei depends on maintenance and expression of its kinetoplast (kDNA), the mitochondrial genome of this parasite and a putative target for veterinary and human antitrypanosomatid drugs. However, the closely related animal pathogens T. evansi and T. equiperdum are transmitted independently of tsetse flies and survive without a functional kinetoplast for reasons that have remained unclear. Here, we provide definitive evidence that single amino acid changes in the nuclearly encoded F ₁F O–ATPase subunit γ can compensate for complete physical loss of kDNA in these parasites. Our results provide insight into the molecular mechanism of compensation for kDNA loss by showing F O-independent generation of the mitochondrial membrane potential with increased dependence on the ADP/ATP carrier. Our findings also suggest that, in the pathogenic bloodstream stage of T. brucei , the huge and energetically demanding apparatus required for kDNA maintenance and expression serves the production of a single F ₁F O–ATPase subunit. These results have important implications for drug discovery and our understanding of the evolution of these parasites.