Suchergebnisse

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. ; We acknowledge support from the German Research Foundation (DFG) under the Emmy Noether Programme (PE 2053/1-1 to F.P. and J.W.), the Munich Center for Systems Neurology (SyNergy EXC 1010 to F.P.), the Juniorverbund in der Systemmedizin "mitOmics" (FKZ 01ZX1405B to V.G. and A.L.), The Bert L & N Kuggie Vallee Foundation (to F.P. and D.M.A.), the DFG (MO1944/1-2 to D.M.), the Spanish Ministry of Economy, Industry, and Competitiveness (MEIC; BFU2015-67107), the European Union's Horizon 2020 research and innovation program under grant agreement ERC-2016-724173 (to T.G. and A.A.P.), and the NIH (RO1 GM102724 to G.H.).