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MICU1 drives glycolysis and chemoresistance in ovarian cancer
Open accessAbstract
Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca 2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.
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Role of calcium ions in regulation of mammalian intramitochondrial metabolism
McCormack, J. G., Halestrap, A. P., & Denton, R. M. (1990) · Physiological Reviews · doi:10.1152/physrev.1990.70.2.391 · Cited by 1,398
Superoxide generation by complex III: From mechanistic rationales to functional consequences
Bleier, L., & Dröse, S. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.12.002 · Cited by 369
MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration
Antony, A. N., Paillard, M., Moffat, C., Juskeviciute, E., Correnti, J., Bolon, B., Rubin, E., Csordás, G., Seifert, E. L., Hoek, J. B., et al. (2016) · Nature Communications · doi:10.1038/ncomms10955 · Cited by 206
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The machineries, regulation and cellular functions of mitochondrial calcium
Giorgi, C., Marchi, S., & Pinton, P. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0052-8 · Cited by 941
Mitochondrial calcium exchange in physiology and disease
Garbincius, J. F., & Elrod, J. W. (2022) · Physiological Reviews · doi:10.1152/physrev.00041.2020 · Cited by 412
Marchi, S., Giorgi, C., Galluzzi, L., & Pinton, P. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.017 · Cited by 235
Metadata
- Authors
- Chakraborty, P. K., Mustafi, S. B., Xiong, X., Dwivedi, S. K. D., Nesin, V., Saha, S., Zhang, M., Dhanasekaran, D., Jayaraman, M., Mannel, R., Moore, K., McMeekin, S., Yang, D., Zuna, R., Ding, K., Tsiokas, L., Bhattacharya, R., & Mukherjee, P.
- Venue
- Nature Communications
- Published
- 2017-05-22
- Volume
- 8
- Issue
- 1
- Pages
- 14634-14634
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2617766232
- Cited by
- 169
- References
- 3
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- gold
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- Chakraborty, P. K., Mustafi, S. B., Xiong, X., Dwivedi, S. K. D., Nesin, V., Saha, S., Zhang, M., Dhanasekaran, D., Jayaraman, M., Mannel, R., Moore, K., McMeekin, S., Yang, D., Zuna, R., Ding, K., Tsiokas, L., Bhattacharya, R., & Mukherjee, P. (2017). MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nature Communications. https://doi.org/10.1038/ncomms14634
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