Journal
CELL METABOLISM
Volume 20, Issue 4, Pages 662-669Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2014.07.024
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Funding
- Deutsche Forschungsgemeinschaft [GRK 1478]
- Excellence Initiative of the German Federal Government [EXC 294 BIOSS, GSC-4]
- Excellence Initiative of the German State Government [EXC 294 BIOSS, GSC-4]
- Baden-Wurttemberg-Stiftung
- Swedish Research Council
- Swedish Alzheimer foundation
- Fundacao para a Ciencia e a Tecnologia
- Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen
- FWF [LIPOTOX, I1000, P23490-B12, P24381-B20]
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Most mitochondrial proteins possess N-terminal presequences that are required for targeting and import into the organelle. Upon import, presequences are cleaved off by matrix processing peptidases and subsequently degraded by the peptidasome Cym1/PreP, which also degrades Amyloid-beta peptides (A beta). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, A beta inhibits degradation of presequence peptides by PreP, resulting in accumulation of mitochondrial preproteins and processing intermediates. Dysfunctional preprotein maturation leads to rapid protein degradation and an imbalanced organellar proteome. Our findings reveal a general mechanism by which A beta peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer's disease.
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