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

Markus Habich | Zendy; Silja Lucia Salscheider | Zendy; Lena Maria Murschall | Zendy; Michaela Nicole Hoehne | Zendy; M. Dominik Fischer | Zendy; Fabian Schorn | Zendy; Carmelina Petrungaro | Zendy; Muna Ali | Zendy; Alican J. Erdogan | Zendy; Shadi Abou-Eid | Zendy; Hamid Kashkar | Zendy; Jörn Dengjel | Zendy; Jan Riemer | Zendy

Open Access

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

Author(s) -

Markus Habich,

Silja Lucia Salscheider,

Lena Maria Murschall,

Michaela Nicole Hoehne,

M. Dominik Fischer,

Fabian Schorn,

Carmelina Petrungaro,

Muna Ali,

Alican J. Erdogan,

Shadi Abou-Eid,

Hamid Kashkar,

Jörn Dengjel,

Jan Riemer

Publication year - 2019

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2018.12.092

Subject(s) - mitochondrial intermembrane space , disulfide bond , cytosol , chaperone (clinical) , oxidoreductase , intermembrane space , microbiology and biotechnology , chemistry , redox , biophysics , metastability , mitochondrion , biochemistry , biology , enzyme , medicine , organic chemistry , escherichia coli , pathology , bacterial outer membrane , gene

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.

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