Schlagowski, Anna M., Knoringer, Katharina ORCID: 0000-0002-1928-2779, Morlot, Sandrine, Sanchez Vicente, Ana, Flohr, Tamara ORCID: 0000-0002-8775-7959, Kraemer, Lena, Boos, Felix ORCID: 0000-0002-1571-9806, Khalid, Nabeel, Ahmed, Sheraz, Schramm, Jana, Murschall, Lena M., Haberkant, Per ORCID: 0000-0002-5608-9062, Stein, Frank, Riemer, Jan, Westermann, Benedikt, Braun, Ralf J., Winklhofer, Konstanze F., Charvin, Gilles and Herrmann, Johannes M. (2021). Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol. Embo J., 40 (16). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

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. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schlagowski, Anna M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knoringer, KatharinaUNSPECIFIEDorcid.org/0000-0002-1928-2779UNSPECIFIED
Morlot, SandrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez Vicente, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flohr, TamaraUNSPECIFIEDorcid.org/0000-0002-8775-7959UNSPECIFIED
Kraemer, LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boos, FelixUNSPECIFIEDorcid.org/0000-0002-1571-9806UNSPECIFIED
Khalid, NabeelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmed, SherazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schramm, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murschall, Lena M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haberkant, PerUNSPECIFIEDorcid.org/0000-0002-5608-9062UNSPECIFIED
Stein, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riemer, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, BenediktUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, Ralf J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winklhofer, Konstanze F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charvin, GillesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-600974
DOI: 10.15252/embj.2021107913
Journal or Publication Title: Embo J.
Volume: 40
Number: 16
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SULFHYDRYL OXIDASE ERV1; DISULFIDE RELAY SYSTEM; INTERMEMBRANE SPACE; QUALITY-CONTROL; ASYMMETRIC INHERITANCE; MEMBRANE-PROTEINS; STRESS-RESPONSE; YEAST; HUNTINGTIN; TRANSLOCATIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60097

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