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

Carmelina Petrungaro; Katharina M Zimmermann; Victoria Küttner; Manuel Fischer; Jörn Dengjel; Ivan Bogeski; Jan Riemer

doi:10.1016/j.cmet.2015.08.019

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

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

Authors

Carmelina Petrungaro¹, Katharina M Zimmermann², Victoria Küttner³, Manuel Fischer⁴, Jörn Dengjel³, Ivan Bogeski², Jan Riemer⁵

Affiliations

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.

PMID: 26387864
DOI: 10.1016/j.cmet.2015.08.019

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcium / metabolism*
Calcium Channels / chemistry
Calcium Channels / metabolism*
Calcium-Binding Proteins / antagonists & inhibitors
Calcium-Binding Proteins / chemistry
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Cation Transport Proteins / antagonists & inhibitors
Cation Transport Proteins / chemistry
Cation Transport Proteins / genetics
Cation Transport Proteins / metabolism*
Dimerization
Disulfides / chemistry
Disulfides / metabolism
HEK293 Cells
HeLa Cells
Humans
Ions / chemistry
Ions / metabolism
Mitochondria / metabolism*
Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
Mitochondrial Membrane Transport Proteins / chemistry
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism*
Mitochondrial Precursor Protein Import Complex Proteins
RNA Interference
RNA, Small Interfering / metabolism

Substances

CHCHD4 protein, human
Calcium Channels
Calcium-Binding Proteins
Cation Transport Proteins
Disulfides
Ions
MICU1 protein, human
MICU2 protein, human
Mitochondrial Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
RNA, Small Interfering
Calcium