Encoding of the colorectal cancer metabolic program through MICU2

Summary The mitochondrial Ca 2+ uniporter (MCU) plays crucial role in intramitochondrial Ca 2+ uptake, allowing Ca 2+ -dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and migration using in vitro and in vivo models of colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca 2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming. Highlights MICU2 plays a pivotal role in the balance between anaerobic glycolysis and oxidative phosphorylation MICU2 stabilizes the mitochondrial network and endoplasmic reticulum–mitochondrial calcium flux MICU2 expression and the MICU2/MICU1 ratio control proliferation and metastasis formation in colorectal cancer Graphical Abstract