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Cell Metab. 2015 Oct 6;22(4):721-33. doi: 10.1016/j.cmet.2015.08.019. Epub 2015 Sep 17.

The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake.

Author information

1
Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany; Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, 50674 Cologne, Germany.
2
Department of Biophysics, CIPMM, School of Medicine, University of Saarland, 66421, Homburg, Germany.
3
Department of Dermatology, Medical Center, Freiburg Institute for Advanced Studies, BIOSS Centre for Biological Signaling Studies, ZBSA Center for Biological Systems Analysis, University of Freiburg, Habsburgerstr. 49, 79104 Freiburg, Germany.
4
Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany.
5
Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany; Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, 50674 Cologne, Germany. Electronic address: jan.riemer@uni-koeln.de.

Abstract

The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.

KEYWORDS:

CHCHD4; Ca(2+); MCUx; MICU; Mia40; disulfide; mitochondria; redox

PMID:
26387864
DOI:
10.1016/j.cmet.2015.08.019
[Indexed for MEDLINE]
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