Novel mechanisms of bacterial proteins in mitochondrial dysfunction and disease

• Applicant: Dr. Sabrina Mühlen
• Subject Area: Cell Biology
• Term: from 2010 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 168265562

A common strategy of pathogens relates to the subversion of host mitochondrial function by targeting ‘effector’ proteins to these organelles. While most studies examine this process in relation to the organelle’s role in controlling cell death, other mitochondrial functions such as ATP/metabolite production, calcium/reactive oxygen species homeostasis and autophagy are neglected. Enteropathogenic Escherichia coli (EPEC)-induced diarrhea depends on a secretion system that delivers over 20 effector proteins, of which two (Map/EspF) have functional Mitochondrial-Targeting Sequences (MTS) and are known to alter mitochondrial function. Unexpectedly, our studies unlinked mitochondrial dysfunction with Map/EspF targeting these organelles and instead implicated extra-mitochondrial functions of Map/EspF, cytoskeletatal arrangements and a role for serine phosphorylation of the plasma membrane-located effector (Tir). The proposed study will use effector variants in cellular biological, fluorescent imaging/quantification and biochemical studies to define the molecular mechanism(s) by which these effectors subvert mitochondrial functions. Assays will be developed to monitor many of these functions in order to assess the impact of EPEC subversion on these processes and their contribution to triggering ‘hallmark’ events that define the EPEC diarrheal process. Studies will also interrogate the idea that pathogens subvert mitochondrial function as a novel mechanism for spatiotemporal regulation of the activity of MTS-carrying proteins.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Brendan Kenny