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Wettmarshausen, J. ; Goh, V. ; Huang, K.T.* ; Arduino, D.M. ; Tripathi, U.* ; Leimpek, A. ; Cheng, Y. ; Pittis, A.A.* ; Gabaldón, T.* ; Mokranjac, D.* ; Hajnóczky, G.* ; Perocchi, F.

MICU1 confers protection from MCU-dependent manganese toxicity.

Cell Rep. 25, 1425-1435 (2018)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The mitochondrial calcium uniporter is a highly selective ion channel composed of species-and tissue-specific subunits. However, the functional role of each component still remains unclear. Here, we establish a synthetic biology approach to dissect the interdependence between the pore-forming subunit MCU and the calcium-sensing regulator MICU1. Correlated evolutionary patterns across 247 eukaryotes indicate that their co-occurrence may have conferred a positive fitness advantage. We find that, while the heterologous reconstitution of MCU and EMRE in vivo in yeast enhances manganese stress, this is prevented by co-expression of MICU1. Accordingly, MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. As a result, manganese overload increases oxidative stress, which can be effectively prevented by NAC treatment. Our study identifies a critical contribution of MICU1 to the uniporter selectivity, with important implications for patients with MICU1 deficiency, as well as neurological disorders arising upon chronic manganese exposure.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Mcu ; Micu1 ; Calcium ; Manganese ; Mitochondria ; Signaling ; Yeast; Mitochondrial Calcium Uniporter; Rat-kidney Mitochondria; Ca2+ Uptake; Liver Mitochondria; Ef-hand; Yeast; Binding; Proteins; Ion; Identification
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 25, Heft: 6, Seiten: 1425-1435 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)