Deciphering mitochondrial quality control in Trypanosoma brucei

Time: To be announced
Where:
To be announced
Dr Caroline Dewar

Authors

C E Dewar1; S Oeljeklaus2; B Warscheid2; A Schneider1
1 University of Bern, Switzerland;  2 University of Freiburg, Germany

Discussion

Mitochondrial quality control (MQC) is the network of pathways by which eukaryotic cells monitor and maintain the function of their mitochondria. Trypanosoma brucei has a large single mitochondrion, which prevents the elimination of dysfunctional mitochondria as in some other organisms. When this essential mitochondrion is not functioning correctly, for example when mitochondrial protein import is defective, cell viability suffers. The processes by which this parasite regulates its mitochondrial function are of great interest, particularly in relation to its life cycle, where the mitochondrion undergoes massive programmed morphological and functional alterations.

MQC pathways in yeast and metazoa are regulated on the transcriptional level. However, in T. brucei, due to polycistronic transcription, MQC regulation in this way is not possible. Additionally, other than ubiquitin and the proteasome, orthologues of most common MQC factors found in yeast and metazoa are absent in T. brucei. Mitochondrial biogenesis in general in T. brucei has been shown to be greatly impacted by convergent evolution, and we expect the same to be the case for mechanisms governing MQC.

95% of mitochondrial proteins in T. brucei are encoded in the nuclear DNA. The multisubunit ATOM complex is the mediator of protein import through the mitochondrial outer membrane in trypanosomes (Pusnik et al., 2011, Mani et al., 2015). We previously defined the T. brucei mitochondrial importome as being the proteins which decreased in level when ATOM40, the central import pore, was knocked down (Peikert et al., 2017). We will show data demonstrating the existence of a MQC pathway in T. brucei triggered when mitochondrial protein import is blocked, where the endpoint is the proteasomal degradation of specifically mislocalised mitochondrial proteins. Using a variety of proteomic and biochemical approaches, we show that the proteasome and putative components of a ubiquitin-driven pathway are recruited to the mitochondrion upon the induction of an import defect. Trypanosomatid-specific candidates are being investigated as to their roles within this MQC pathway. Of particular interest is a nuclearly-localised protein with a ubiquitin-like domain which is released into the cytoplasm upon the induction of a mitochondrial import defect. Nuclear release of this protein is required for this MQC mechanism to function.

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