Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca2

• Published in: Scientific reports 2015-10, Vol.5 (1), p.15602, Article 15602
• Main Authors: Waldeck-Weiermair, Markus, Malli, Roland, Parichatikanond, Warisara, Gottschalk, Benjamin, Madreiter-Sokolowski, Corina T., Klec, Christiane, Rost, Rene, Graier, Wolfgang F.
• Format: Article
• Language: English
• Subjects: 14; 14/10; 14/33; 14/63; 631/80/642/333; 631/80/86/1999; Calcium (mitochondrial); Calcium influx; Calcium signalling; EF-hand; Fluorescence resonance energy transfer; Histamine; Humanities and Social Sciences; Membrane potential; Mitochondria; multidisciplinary; Proteins; Science
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep15602

Mitochondrial Ca 2+ uptake is a vital process that controls distinct cell and organelle functions. Mitochondrial calcium uptake 1 (MICU1) was identified as key regulator of the mitochondrial Ca 2+ uniporter (MCU) that together with the essential MCU regulator (EMRE) forms the mitochondrial Ca 2+ channel. However, mechanisms by which MICU1 controls MCU/EMRE activity to tune mitochondrial Ca 2+ signals remain ambiguous. Here we established a live-cell FRET approach and demonstrate that elevations of cytosolic Ca 2+ rearranges MICU1 multimers with an EC 50 of 4.4 μM, resulting in activation of mitochondrial Ca 2+ uptake. MICU1 rearrangement essentially requires the EF-hand motifs and strictly correlates with the shape of cytosolic Ca 2+ rises. We further show that rearrangements of MICU1 multimers were independent of matrix Ca 2+ concentration, mitochondrial membrane potential and expression levels of MCU and EMRE. Our experiments provide novel details about how MCU/EMRE is regulated by MICU1 and an original approach to investigate MCU/EMRE activation in intact cells.