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

• Published in: Cell metabolism 2015-10, Vol.22 (4), p.721-733
• Main Authors: Petrungaro, Carmelina, Zimmermann, Katharina M, Küttner, Victoria, Fischer, Manuel, Dengjel, Jörn, Bogeski, Ivan, Riemer, Jan
• Format: Article
• Language: English
• Subjects: 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; RNA Interference; RNA, Small Interfering - metabolism
• ISSN: 1932-7420
• DOI: 10.1016/j.cmet.2015.08.019

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.