Characterizing a multi-protein sensor of mitochondrial damage regulating membrane dynamics, mitochondrial integrity and auto/mitophagy

Prof. Ralf Baumeister (Institute of Biology III)

The Parkinson´s Diesease (PD) gene pink-1 encodes a mitochondrial protein that, in combination with the UPRmt, records mitochondrial damage and recruits the PD factor Parkin to turn-over damaged subcompartments by fission/fusion. It also may represent the switch that, upon extensive damage to mitochondria, results in their destruction and recycling through mitochondrial autophagy (mitophagy involving fusion of mitochondrial and lysosomal membranes). In C. elegans we identified the large cytosolic protein LRK-1, ortholog of human kinase/GTPases LRRK1 and LRRK2, localized at the lysosomal membrane, as an antagonist of PINK-1 that rescues the mitochondrial abnormalities observed in pink-1 mutants. In this project we will use the established methods and markers of mitochondrial stress signaling for the functional characterization of the complex genetic and protein interaction network of PINK1 and LRRK2/LRK-1. We hypothesize that PINK1 and LRRK2 antagonicity constitutes a molecular sensor responding to mitochondrial damage or depolarization. This sensor affects intracellular dynamics, membrane localization, and the inducibility of stress pathways and controls the switch to mitochondrial fusion and mitophagy to protect the cell.