PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca2+ uptake in immortalized cells

• Published in: Nature communications Vol. 7; no. 1; pp. 12897 - 13
• Main Authors: Madreiter-Sokolowski, Corina T., Klec, Christiane, Parichatikanond, Warisara, Stryeck, Sarah, Gottschalk, Benjamin, Pulido, Sergio, Rost, Rene, Eroglu, Emrah, Hofmann, Nicole A., Bondarenko, Alexander I., Madl, Tobias, Waldeck-Weiermair, Markus, Malli, Roland, Graier, Wolfgang F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.09.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/89; 14/19; 14/33; 14/35; 14/63; 631/80/2373/2238; 631/80/642/333; 631/80/86/1999; 96/95; Humanities and Social Sciences; multidisciplinary; Proteins; Science; Science (multidisciplinary); Austria; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12897

Recent studies revealed that mitochondrial Ca 2+ channels, which control energy flow, cell signalling and death, are macromolecular complexes that basically consist of the pore-forming mitochondrial Ca 2+ uniporter (MCU) protein, the essential MCU regulator (EMRE), and the mitochondrial Ca 2+ uptake 1 (MICU1). MICU1 is a regulatory subunit that shields mitochondria from Ca 2+ overload. Before the identification of these core elements, the novel uncoupling proteins 2 and 3 (UCP2/3) have been shown to be fundamental for mitochondrial Ca 2+ uptake. Here we clarify the molecular mechanism that determines the UCP2/3 dependency of mitochondrial Ca 2+ uptake. Our data demonstrate that mitochondrial Ca 2+ uptake is controlled by protein arginine methyl transferase 1 (PRMT1) that asymmetrically methylates MICU1, resulting in decreased Ca 2+ sensitivity. UCP2/3 normalize Ca 2+ sensitivity of methylated MICU1 and, thus, re-establish mitochondrial Ca 2+ uptake activity. These data provide novel insights in the complex regulation of the mitochondrial Ca 2+ uniporter by PRMT1 and UCP2/3. MICU1 is a regulatory subunit of mitochondrial Ca 2+ channels that shields mitochondria from Ca 2+ overload. Here the authors show that MICU1 methylation by PRMT1 reduces Ca 2+ sensitivity, which is normalized by UCP2/3, re-establishing mitochondrial Ca 2+ uptake activity.