Molecular and cellular mechanisms to protect against the accumulation of protein aggregates in mitochondria

• Applicant: Professor Dr. Wolfgang Voos
• Subject Area: Biochemistry
• Term: from 2007 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 37190627

The grant proposal addresses the biochemical and cell biological reactions that deal with mitochondria-specific protein aggregation processes. The planned experiments will cover three important aspects of potential protective mechanisms: I) A detailed biochemical characterization of the functional protein quality control network formed by the endogenous mitochondrial chaperone enzymes and ATP-dependent proteases; II) the determination of proteo-toxic reactions induced by aggregate accumulation in mitochondria that interfere with the essential mechanisms that maintain protein homeostasis; and III) establishing the impact of novel aggregation-protective mechanisms, in particular aggregate sequestration and mitophagy for their relevance in the mitochondrial system. The focus will be set on a biochemical analysis of the endogenous mitochondrial protein system under conditions that most closely retain the in vivo situation. For this purpose we will utilize specifically developed assays for mitochondrial aggregation and disaggregation reactions in intact isolated mitochondria as well as quantitative proteomic approaches to follow the behavior of as many endogenous proteins as possible. Of particular interest will be the determination of the mechanism of functional cooperation between the mitochondrial chaperone Hsp78 (or alternatively mtHsp70 in higher eukaryotes), as a crucial mediator of disaggregation reactions with the LON/Pim1 quality control protease in the mitochondrial matrix. The planned experiments will utilize the yeast model system for basic biochemical assays but extent the research on the characterization of aggregation reaction in mammalian cell system to provide novel information on the role of mitochondrial protein homeostasis in the etiology of human neurodegenerative diseases.

• DFG Programme: Research Grants