Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol
Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol
Abstract The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis. (174/175 words)
Winklhofer Konstanze F.、Herrmann Johannes M.、Khalid Nabeel、Haberkant Per、Schlagowski Anna M.、Morlot Sandrine、S¨￠chez Vicente Ana、Ahmed Sheraz、Braun Ralf J.、Schramm Jana、Kn?ringer Katharina、Charvin Gilles、Murschall Lena Maria、Westermann Benedikt、Boos Felix、Riemer Jan、Stein Frank
Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University BochumCell Biology, University of KaiserslauternGerman Research Center for Artificial Intelligence DFKIProteomics Core Facility, EMBL HeidelbergCell Biology, University of KaiserslauternInstitut de G¨|n¨|tique et de Biologie Mol¨|culaire et Cellulaire||Centre National de la Recherche Scientifique||Institut National de la Sant¨| et de la Recherche M¨|dicale||Universit¨| de StrasbourgDepartment of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University BochumGerman Research Center for Artificial Intelligence DFKICell Biology, University of Bayreuth||Neurodegeneration, Danube Private UniversityCell Biology, University of BayreuthCell Biology, University of KaiserslauternInstitut de G¨|n¨|tique et de Biologie Mol¨|culaire et Cellulaire||Centre National de la Recherche Scientifique||Institut National de la Sant¨| et de la Recherche M¨|dicale||Universit¨| de StrasbourgBiochemistry, University of CologneCell Biology, University of BayreuthCell Biology, University of KaiserslauternBiochemistry, University of CologneProteomics Core Facility, EMBL Heidelberg
基础医学分子生物学神经病学、精神病学
HuntingtinMia40MitochondriaProtein aggregationProtein translocation
Winklhofer Konstanze F.,Herrmann Johannes M.,Khalid Nabeel,Haberkant Per,Schlagowski Anna M.,Morlot Sandrine,S¨￠chez Vicente Ana,Ahmed Sheraz,Braun Ralf J.,Schramm Jana,Kn?ringer Katharina,Charvin Gilles,Murschall Lena Maria,Westermann Benedikt,Boos Felix,Riemer Jan,Stein Frank.Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/2021.02.02.429331.点此复制
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