Micu2, short for mitochondrial calcium uptake 2, is a key regulatory protein of the mitochondrial calcium uniporter (MCU) complex. It plays a crucial role in mitochondrial calcium (mCa2+) uptake, which is fundamental for cellular metabolism, signaling, and survival [2,4,6]. The MCU complex, with Micu2 as one of its components, is involved in the process of activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that could lead to mitochondrial and cellular injury [3].

In colorectal cancer, transcriptomic analysis showed increased MICU2 expression and MICU2/MICU1 ratio in advanced stages and metastases. Its expression is necessary for mitochondrial Ca2+ uptake and mitochondrial network quality, enhancing tumor aggressiveness and metabolic reprogramming [1]. In pancreatic β cells, siRNA silencing of Micu2 in cell lines and Micu2 knockout in mice abrogated glucose-stimulated insulin secretion (GSIS), as MICU2 is critical for β cell mitochondrial Ca2+ uptake [5]. In the mammalian heart, MICU1 and MICU2 together control cardiac mitochondrial Ca2+ influx, and genetic models have shown that MICU1 deletion causes compensatory changes in the MCU complex, highlighting the importance of MICU2 in maintaining proper cardiac mitochondrial function [3].

In summary, Micu2 is essential for mitochondrial Ca2+ uptake, influencing processes like insulin secretion, cancer development, and cardiac function. Gene knockout mouse models have been instrumental in revealing its role in these biological processes and disease conditions, such as colorectal cancer, diabetes-related insulin secretion disorders, and cardiac mitochondrial function-related diseases.

References:

1. Robert, Alison, Crottès, David, Bourgeais, Jérôme, Raoul, William, Guéguinou, Maxime. 2024. MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development. In PLoS biology, 22, e3002854. doi:10.1371/journal.pbio.3002854. https://pubmed.ncbi.nlm.nih.gov/39466877/

2. Garbincius, Joanne F, Elrod, John W. 2021. Mitochondrial calcium exchange in physiology and disease. In Physiological reviews, 102, 893-992. doi:10.1152/physrev.00041.2020. https://pubmed.ncbi.nlm.nih.gov/34698550/

3. Hasan, Prottoy, Berezhnaya, Elena, Rodríguez-Prados, Macarena, Elrod, John W, Hajnóczky, György. 2024. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2402491121. doi:10.1073/pnas.2402491121. https://pubmed.ncbi.nlm.nih.gov/39163336/

4. Fan, Minrui, Zhang, Jinru, Tsai, Chen-Wei, Tsai, Ming-Feng, Feng, Liang. 2020. Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex. In Nature, 582, 129-133. doi:10.1038/s41586-020-2309-6. https://pubmed.ncbi.nlm.nih.gov/32494073/

5. Vishnu, N, Hamilton, A, Bagge, A, Nicholls, D G, Mulder, H. 2021. Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion. In Molecular metabolism, 51, 101239. doi:10.1016/j.molmet.2021.101239. https://pubmed.ncbi.nlm.nih.gov/33932586/

6. Pathak, Trayambak, Trebak, Mohamed. 2018. Mitochondrial Ca2+ signaling. In Pharmacology & therapeutics, 192, 112-123. doi:10.1016/j.pharmthera.2018.07.001. https://pubmed.ncbi.nlm.nih.gov/30036491/