RT Journal Article
SR Electronic
T1 Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.02.429331
DO 10.1101/2021.02.02.429331
A1 Anna M. Schlagowski
A1 Katharina Knöringer
A1 Sandrine Morlot
A1 Ana Sáchez Vicente
A1 Felix Boos
A1 Nabeel Khalid
A1 Sheraz Ahmed
A1 Jana Schramm
A1 Lena Maria Murschall
A1 Per Haberkant
A1 Frank Stein
A1 Jan Riemer
A1 Benedikt Westermann
A1 Ralf J. Braun
A1 Konstanze F. Winklhofer
A1 Gilles Charvin
A1 Johannes M. Herrmann
YR 2021
UL http://biorxiv.org/content/early/2021/02/02/2021.02.02.429331.abstract
AB 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)Competing Interest StatementThe authors have declared no competing interest.