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Cell Rep. 2019 Jan 15;26(3):759-774.e5. doi: 10.1016/j.celrep.2018.12.092.

Vectorial Import via a Metastable Disulfide-Linked Complex Allows for a Quality Control Step and Import by the Mitochondrial Disulfide Relay.

Author information

1
Institute for Biochemistry, Department of Chemistry, University of Cologne, Zuelpicher Str. 47a/R. 3.49, 50674 Cologne, Germany.
2
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
3
Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
4
Institute for Biochemistry, Department of Chemistry, University of Cologne, Zuelpicher Str. 47a/R. 3.49, 50674 Cologne, Germany. Electronic address: jan.riemer@uni-koeln.de.

Abstract

Disulfide formation in the mitochondrial intermembrane space (IMS) is an essential process. It is catalyzed by the disulfide relay machinery, which couples substrate import and oxidation. The machinery relies on the oxidoreductase and chaperone CHCHD4-Mia40. Here, we report on the driving force for IMS import and on a redox quality control mechanism. We demonstrate that unfolded reduced proteins, upon translocation into the IMS, initiate formation of a metastable disulfide-linked complex with CHCHD4. If this interaction does not result in productive oxidation, then substrates are released to the cytosol and degraded by the proteasome. Based on these data, we propose a redox quality control step at the level of the disulfide-linked intermediate that relies on the vectorial nature of IMS import. Our findings also provide the mechanistic framework to explain failures in import of numerous human disease mutants in CHCHD4 substrates.

KEYWORDS:

CHCHD4; Mia40; disulfide formation; disulfide relay; intermembrane space; oxidative folding; proteasome; quality control; vectorial import

PMID:
30650365
DOI:
10.1016/j.celrep.2018.12.092
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