Mitochondrial stress response in neurodegeneration and aging: OMI and DJ-1 mediated signalling pathways

Coordinator:		Prof. Dr. Rejko Krüger
Institution:		Labor für Funktionelle Neurogenomik, Zentrum für Neurologie und Hertie-Insitut für Klinische Hirnforschung , Universität Tübingen
Homepage:		www.uni-tuebingen.de/

Mitochondrial homeostasis plays a crucial role in ageing and programmed cell death, and recent data from the functional characterization of genetic forms of Parkinson’s disease (PD) suggest that mitochondrial dysfunction is critically related to neurodegeneration. This subproject specifically addresses the role of PD-associated proteins at the mitochondrial interface and aims to dissect intramitochondrial signalling pathways involved in cellular stress response and initiation of cell death mechanisms. The application represents a direct advancement of our findings during the NGFN2 funding period, that underscored the critical modulation of mitochondrial function by mutant Omi/HtrA2 and DJ-1 and identified lifespan-regulating proteins as intramitochondrial targets of these proteins. Using transgenic animal models and primary cell culture based experiments (Omi/HtrA2, DJ-1) we now translate our findings into the in vivo situation to decipher molecular mechanisms involved in mitochondrial homeostasis and stress response. Mitochondrial function will be monitored at different steps of the stress signalling cascade (reactive oxygen species, mitochondrial membrane potential, apoptosis) in relation to modulation of gene expression and toxic insult. Effects on dynamic morphological alterations and subcellular trafficking of mitochondria will be studied. Activation and pharmacological modulation of mitochondrial autophagy will be investigated in primary cell culture (Omi/HtrA2, DJ-1 and Mortalin). These experiments allow the identification of upstream mechanisms initiating cell death pathways in aging and neurodegeneration and therefore allow identification and validation of novel therapeutic targets.




Mitochondrial network in a primary mouse fibroblast.
Mitotracker staining of mitochondria (green) reveals highly interconnected mitochondria in a primary mouse fibroblast. High proportion of branched mitochondria is a prerequisite of normal functioning in primary fibroblasts. Nucleus of the cell is indicated in blue (Hoechst staining).