科研之友
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摘要
The sleeping sickness parasite Trypanosoma brucei has a complex life cycle, alternating between a mammalian host and the tsetse fly vector. A tightly controlled developmental programme ensures parasite transmission between hosts as well as survival within them and involves strict regulation of mitochondrial activities. In the glucose-rich bloodstream, the replicative 'slender' stage is thought to produce ATP exclusively via glycolysis and uses the mitochondrial F1FO-ATP synthase as an ATP hydrolysis-driven proton pump to generate the mitochondrial membrane potential (Delta Psi m). The 'procyclic' stage in the glucose-poor tsetse midgut depends on mitochondrial catabolism of amino acids for energy production, which involves oxidative phosphorylation with ATP production via the F1FO-ATP synthase. Both modes of the F1FO enzyme critically depend on F-O subunit a, which is encoded in the parasite's mitochondrial DNA (kinetoplast or kDNA). Comparatively little is known about mitochondrial function and the role of kDNA in non-replicative 'stumpy' bloodstream forms, a developmental stage essential for disease transmission. Here we show that the L262P mutation in the nuclear-encoded F1 subunit. that permits survival of 'slender' bloodstream forms lacking kDNA ('akinetoplastic' forms), via F-O-independent generation of Delta Psi m, also permits their differentiation into stumpy forms. However, these akinetoplastic stumpy cells lack a Delta Psi m and have a reduced lifespan in vitro and in mice, which significantly alters the withinhost dynamics of the parasite. We further show that generation of Delta Psi m in stumpy parasites and their ability to use a-ketoglutarate to sustain viability depend on F1-ATPase activity. Surprisingly, however, loss of Delta Psi m does not reduce stumpy life span. We conclude that the L262P. subunit mutation does not enable F-O-independent generation of Delta Psi m in stumpy cells, most likely as a consequence of mitochondrial ATP production in these cells. In addition, kDNA-encoded genes other than F-O subunit a are important for stumpy form viability.
- 出版日期2018-7
