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

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Mitochondrial presequence processing plays a central role in mitochondrial protein biogenesis and proteostasis. The essential mitochondrial processing peptidase MPP cleaves the presequence peptides of the vast majority of incoming precursor proteins upon their import from the cytosol. The cleaved presequences are subsequently degraded by the Cym1/PreP oligopeptidase. Impaired MPP activity triggers a mitochondrial stress response, however, the signaling and implementation mechanisms to balance mitochondrial dysfunctions during this stress response are largely unknown. Mutations in MPP and a decline in PreP activity have been implicated in epilepsy and Alzheimer's disease, the pathological mechanisms and pathophysiological consequences remain yet elusive. The objective of this Emmy-Noether-research proposal is the comprehensive analysis of the mitochondrial proteases MPP and Cym1/PreP. To this end I will (i) analyze the mitochondrial stress response induced upon MPP impairment, (ii) dissect the pathophysiological consequences of a mutation in MPP resulting in epilepsy in humans and (iii) investigate turnover of Amyloid-beta peptides by Cym1/PreP and the pathological mechanism of mitochondrial Amyloid-beta in Alzheimer's disease. I will combine in vitro, in organello and in vivo approaches using different model organisms (yeast, tissue culture, mice and patient-derived cells) to decipher these novel roles of the mitochondrial presequence processing machinery in health and disease. The MPP-linked stress response will be investigated using global proteomic and transcriptomic analysis, followed by detailed molecular and functional analysis of the involved mitochondrial proteins. The consequences of MPP dysfunction and its mitigation by mitochondrial-nucleus signaling and stress response induction will also be highly valuable for the understanding of MPP dysfunction in human diseases. In particular I aim to mechanistically analyze an epilepsy-causing mutation in the MPP subunit PMPCB by biochemical and cell biological approaches. The pathophysiological consequences of this mutation will be deciphered using patient-derived induced pluripotent stem cells and long-term neuro-epithelial stem cells. The role of mitochondria in the pathogenesis of Alzheimer's disease will be scrutinized using an in vivo model that enables assessment of the toxicity of various Amyloid-beta species and investigation of their degradation by the mitochondrial oligopeptidases Cym1/PreP and Ste23/IDE. Resulting data will be transferred onto human tissue culture cells and mouse models to decipher the role of the mitochondrial presequence turnover machinery in the pathogenesis and progression of Alzheimer's disease. Taken together, this Emmy-Noether-proposal aims to uncover the mechanistic principles in mitochondrial stress signaling and response and in the pathogenesis of neurological disorders induced by a dysfunctional mitochondrial presequence processing machinery.