Universität zu Köln

Murschall, Lena Maria, Gerhards, Anne, MacVicar, Thomas, Peker, Esra, Hasberg, Lidwina, Wawra, Stephan, Langer, Thomas and Riemer, Jan (2020). The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import. BMC Biol., 18 (1). LONDON: BMC. ISSN 1741-7007

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Abstract

Background The mitochondrial intermembrane space (IMS) is home to proteins fulfilling numerous essential cellular processes, particularly in metabolism and mitochondrial function. All IMS proteins are nuclear encoded and synthesized in the cytosol and must therefore be correctly targeted and transported to the IMS, either through mitochondrial targeting sequences or conserved cysteines and the mitochondrial disulfide relay system. The mitochondrial oxidoreductase MIA40, which catalyzes disulfide formation in the IMS, is imported by the combined action of the protein AIFM1 and MIA40 itself. Here, we characterized the function of the conserved highly negatively charged C-terminal region of human MIA40. Results We demonstrate that the C-terminal region is critical during posttranslational mitochondrial import of MIA40, but is dispensable for MIA40 redox function in vitro and in intact cells. The C-terminal negatively charged region of MIA40 slowed import into mitochondria, which occurred with a half-time as slow as 90 min. During this time, the MIA40 precursor persisted in the cytosol in an unfolded state, and the C-terminal negatively charged region served in protecting MIA40 from proteasomal degradation. This stabilizing property of the MIA40 C-terminal region could also be conferred to a different mitochondrial precursor protein, COX19. Conclusions Our data suggest that the MIA40 precursor contains the stabilizing information to allow for postranslational import of sufficient amounts of MIA40 for full functionality of the essential disulfide relay. We thereby provide for the first time mechanistic insights into the determinants controlling cytosolic surveillance of IMS precursor proteins.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Murschall, Lena Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerhards, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED MacVicar, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Peker, Esra UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasberg, Lidwina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wawra, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Riemer, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-323777
DOI:	10.1186/s12915-020-00824-1
Journal or Publication Title:	BMC Biol.
Volume:	18
Number:	1
Date:	2020
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1741-7007
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTERMEMBRANE SPACE; DISULFIDE RELAY; PROTEIN; SYSTEM; HEALTH; CHCHD4; AIF Multiple languages Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/32377