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Novel roles of the mitochondrial presequence processing machinery in health and disease

Subject Area Biochemistry
Cell Biology
Term from 2016 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 289336601
 
Final Report Year 2022

Final Report Abstract

The aim of this Emmy-Noether project was the comprehensive analysis of the mitochondrial presequence processing machinery under physiological conditions and the investigation of specific pathophysiological aspects as mutations in several subunits have been associated with severe human diseases. Presequences are targeting signals that mediate the import of mitochondrial precursor proteins into the organelle after their synthesis on cytosolic ribosomes. The presequence processing machinery consists of processing proteases that cleave the presequence (MPP, Icp55, Oct1/MIP) and presequence peptidases (Cym1/PreP, Ste23, Prd1) that degrade the presequence. In my Emmy-Noether group we uncovered the peptidases Ste23 and Prd1 and their function in presequence peptide degradation. We also characterized the role of the human homologue Cym1 (PreP) and consequences of defective PreP presequence turnover in human cells (Aim 3). Together with clinicians we identified and described the first patients with mutations in the catalytic subunit of MPP and showed that the patients have defects in functions of iron-sulfur cluster containing proteins (Aim 2). Finally, as proposed in Aim 1 we thoroughly characterized the unfolded protein response that protects yeast upon defects in MPP and identified two key protective mechanisms on the molecular level: The maintenance of mitochondrial gene expression by the transcription factor Rox1 and the role of protein import and lipid remodelling to maintain protein import upon mitochondrial stress conditions.

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