Dataset Information

Increased levels of the mitochondrial import factor Mia40 can 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 these aggregates impaired mitochondrial respiration only slightly, they interfered with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP. Even more surprising, Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on our 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 regulatory component in this competition with direct relevance for cytosolic proteostatic stability. Thus, targeting Mia40 might offer exciting therapeutic potential in the future. In this dataset we analyzed the soluble proteome of wild type and Mia40 overexpression yeast cells in response to the expression of polyQ proteins.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Frank Stein

LAB HEAD: Johannes M. Herrmann

PROVIDER: PXD023902 | Pride | 2021-08-05

REPOSITORIES: Pride

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Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol.

Schlagowski Anna M AM Knöringer Katharina K Morlot Sandrine S Sánchez Vicente Ana A Flohr Tamara T Krämer Lena L Boos Felix F Khalid Nabeel N Ahmed Sheraz S Schramm Jana J Murschall Lena M LM Haberkant Per P Stein Frank F Riemer Jan J Westermann Benedikt B Braun Ralf J RJ Winklhofer Konstanze F KF Charvin Gilles G Herrmann Johannes M JM

The EMBO journal 20210630 16

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Alt ...[more]

PMID: 34191328

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