A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis

Author:

Peker Esra1ORCID,Weiss Konstantin1ORCID,Song Jiyao2ORCID,Zarges Christine1ORCID,Gerlich Sarah1ORCID,Boehm Volker3ORCID,Trifunovic Aleksandra456ORCID,Langer Thomas567ORCID,Gehring Niels H.36ORCID,Becker Thomas2ORCID,Riemer Jan15ORCID

Affiliation:

1. Institute for Biochemistry, University of Cologne 1 , Cologne, Germany

2. Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn 2 , Bonn, Germany

3. Institute for Genetics, University of Cologne 3 , Cologne, Germany

4. Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne 4 , Cologne, Germany

5. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne 5 , Cologne, Germany

6. Center for Molecular Medicine, University of Cologne 6 , Cologne, Germany

7. Max Planck Institute for Biology of Ageing 7 Department of Mitochondrial Proteostasis, , Cologne, Germany

Abstract

Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway linking IMS and matrix import systems. A weak targeting sequence drives TIM23-dependent NDUFAF8 matrix import, and en route, allows exposure to the IMS disulfide relay, which oxidizes NDUFAF8. Import is closely surveyed by proteases: YME1L prevents accumulation of excess NDUFAF8 in the IMS, while CLPP degrades reduced NDUFAF8 in the matrix. Therefore, NDUFAF8 can only fulfil its function in complex I biogenesis if both oxidation in the IMS and subsequent matrix import work efficiently. We propose that the two-step import pathway for NDUFAF8 allows integration of the activity of matrix complex I biogenesis pathways with the activity of the mitochondrial disulfide relay system in the IMS. Such coordination might not be limited to NDUFAF8 as we identified further proteins that can follow such a two-step import pathway.

Funder

Deutsche Forschungsgemeinschaft

Monash University

Publisher

Rockefeller University Press

Subject

Cell Biology

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