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Start of funding 01.07.2007

Mitochondrial protein transport machineries of parasitic protozoa

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Mitochondria from parasitic protozoa differ from mitochondria of higher eukaryotes as far as morphology, metabolism and function are concerned. In silico analyses suggest that many components of the canonical mitochondrial protein transport machineries of yeast and mammals are either not present or significantly different in unicellular parasites. We want to study the protein transport machineries in Leishmania in order to learn more about i) the evolution of transport mechanisms and ii) structure-function relationships of the components involved. Differences in parasite and mammalian machineries may, for example, lead to the identification of targets for drug development. Our first step goal is therefore to establish the large scale purification of mitochondria from the parasite Leishmania tarentolae combining the knowledge of Prof. Simpson’s laboratory at UCLA and Prof. Neupert’s laboratory at LMU with the help of BaCaTeC.

Final report:
Based on two BaCaTeC-funded stays in Larry Simpson’s laboratory at the UCLA in Sept. 2007 and Aug. 2008, I was able to transfer the knowledge on the isolation of mitochondria of the kinetoplastid model parasite Leishmania tarentolae to my junior research group at the LMU in Munich. This knowledge was an excellent starting point for subsequent studies on mitochondrial protein import that were supported by DFG grants DE 1431/2-1 and 2-2 and the Friedrich-Baur-Foundation. Since 2010, the project has continued in my research group at the Dept. of Parasitology in Heidelberg resulting in a key article on mitochondrial protein import in parasitic protists in 2012 (1), two subsequent original publications in 2012 and 2013 (2,3) and two reviews in 2009 and 2012 (4,5). In summary, we established Leishmania tarentolae as a model organism for the comprehensive analysis of protein import into all four mitochondrial compartments. With the help of this system, we showed that a variety of mitochondrial protein import pathways are functionally conserved among eukaryotes despite a significant compositional diversity of the import machineries. In other words, the import signals of different protein classes seem to be sufficiently conserved in the course of evolution whereas the protein receptors and import machineries themselves underwent drastic changes. These findings have important implications. First, generally accepted models on the mitochondrial protein import machineries of opisthokonts (a major eukaryotic lineage that includes yeast and all animals) cannot be simply transferred to other major eukaryotic lineages (that include important parasites). Second, altered or alternative protein import machineries in parasitic protists might serve as a starting point for the development of specific inhibitors.

Heidelberg, 30th of July 2013, Marcel Deponte

(1) Eckers E, Cyrklaff M, Simpson L, and Deponte M. (2012) Mitochondrial protein import pathways are functionally conserved among eukaryotes despite compositional diversity of the import machineries. Biol. Chem. 393:513-24.
(2) Eckers E, Petrungaro C, Groß D, Riemer J, Hell K, and Deponte M. (2013) Divergent molecular evolution of the mitochondrial sulfhydryl:cytochrome c oxidoreductase Erv in opisthokonts and parasitic protists. J. Biol. Chem. 288:2676-88.
(3) Eckers E and Deponte M. (2012) No need for labels: The autofluorescence of Leishmania tarentolae mitochondria and the necessity of negative controls. PLOS ONE 7:e47641.
(4) Deponte M and Hell K. (2009) Disulphide bond formation in the intermembrane space of mitochondria. J. Biochem. 146:599-608.
(5) Deponte M*, Hoppe HC*, Lee M*, Maier AG*, Richard D*, Rug M*, Spielmann T*, and Przyborski JM*. (2012) Wherever I may roam: Protein and membrane trafficking in P. falciparum-infected red blood cells. Mol. Biochem. Parasitol. 186:95-116.