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Open AccessArticle

Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma

1
Institute of Physiology of the Czech Academy of Sciences, Laboratory of Mitochondrial Physiology, 142 20 Prague, Czech Republic
2
Institute of Medical Biochemistry and Laboratory Diagnostics of the General University Hospital and the First Faculty of Medicine, Charles University, 121 08 Prague, Czech Republic
3
Institute of Biophysics and Informatics, the First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
4
Department of Oncology, the General University Hospital and The First Faculty of Medicine, 128 08 Prague, Czech Republic
5
4 th Department of Internal Medicine, the General University Hospital and the First Faculty of Medicine, Charles University, 128 08 Prague , Czech Republic
*
Author to whom correspondence should be addressed.
Academic Editor: David Wong
Cancers 2021, 13(7), 1709; https://doi.org/10.3390/cancers13071709
Received: 26 February 2021 / Revised: 29 March 2021 / Accepted: 1 April 2021 / Published: 4 April 2021
(This article belongs to the Section Molecular Cancer Biology)
2-hydroxyglutarate (2HG) is a metabolite resembling normal cell metabolite 2-oxoglutarate (2OG), however, its accumulation in cells might lead to amplification of processes in cancer development. R-2HG is a product or bi-product of several metabolic enzymes, including mitochondrial ones. We investigated whether production of mitochondrial 2HG is elevated in breast cancer cell lines and identified active competition for initial substrate, 2OG, between enzymes isocitrate dehydrogenase IDH2 and alcohol dehydrogenase ADHFE1. We have also investigated possible substrate and cofactor NADPH channeling between the two IDH2 molecules within mitochondria. We characterized several situations when either IDH2 and ADHFE1 produce a non-negligible amount of 2HG, which is then actively exported from cells. This can serve as a clinical application of our findings. We have therefore quantified 2HG levels in the urine of breast carcinoma patients after resection of their tumors and showed a positive correlations between cancer stages and 2HG levels. Note that cancer stages I to IV differ by the existence and severity of metastases. Extension of these findings might help to improve diagnostic approaches of breast carcinoma.
Mitochondrial production of 2-hydroxyglutarate (2HG) can be catalyzed by wild-type isocitrate dehydrogenase 2 (IDH2) and alcohol dehydrogenase, iron-containing 1 (ADHFE1). We investigated whether biochemical background and substrate concentration in breast cancer cells promote 2HG production. To estimate its role in 2HG production, we quantified 2HG levels and its enantiomers in breast cancer cells using analytical approaches for metabolomics. By manipulation of mitochondrial substrate fluxes using genetic and pharmacological approaches, we demonstrated the existence of active competition between 2HG producing enzymes, i.e., IDH2 and ADHFE1. Moreover, we showed that distinct fractions of IDH2 enzyme molecules operate in distinct oxido-reductive modes, providing NADPH and producing 2HG simultaneously. We have also detected 2HG release in the urine of breast cancer patients undergoing adjuvant therapy and detected a correlation with stages of breast carcinoma development. In summary, we provide a background for vital mitochondrial production of 2HG in breast cancer cells with outcomes towards cancer biology and possible future diagnosis of breast carcinoma. View Full-Text
Keywords: IDH2; 2HG; breast carcinoma IDH2; 2HG; breast carcinoma
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MDPI and ACS Style

Špačková, J.; Gotvaldová, K.; Dvořák, A.; Urbančoková, A.; Pospíšilová, K.; Větvička, D.; Leguina-Ruzzi, A.; Tesařová, P.; Vítek, L.; Ježek, P.; Smolková, K. Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma. Cancers 2021, 13, 1709. https://doi.org/10.3390/cancers13071709

AMA Style

Špačková J, Gotvaldová K, Dvořák A, Urbančoková A, Pospíšilová K, Větvička D, Leguina-Ruzzi A, Tesařová P, Vítek L, Ježek P, Smolková K. Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma. Cancers. 2021; 13(7):1709. https://doi.org/10.3390/cancers13071709

Chicago/Turabian Style

Špačková, Jitka; Gotvaldová, Klára; Dvořák, Aleš; Urbančoková, Alexandra; Pospíšilová, Kateřina; Větvička, David; Leguina-Ruzzi, Alberto; Tesařová, Petra; Vítek, Libor; Ježek, Petr; Smolková, Katarína. 2021. "Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma" Cancers 13, no. 7: 1709. https://doi.org/10.3390/cancers13071709

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