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

0542429 - FGÚ 2022 RIV CH eng J - Článek v odborném periodiku
Špačková, Jitka - Gotvaldová, Klára - Dvořák, Aleš - Urbančoková, Alexandra - Pospíšilová, K. - Větvička, D. - Leguina-Ruzzi, Alberto A. - Tesařová, P. - Vítek, L. - Ježek, Petr - Smolková, Katarína
Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma.
Cancers (Basel). Roč. 13, č. 7 (2021), č. článku 1709. E-ISSN 2072-6694
Grant CEP: GA MZd(CZ) NV19-01-00101; GA ČR(CZ) GA21-01205S
Institucionální podpora: RVO:67985823
Klíčová slova: IDH2 * 2HG * ADHFE1 * breast carcinoma
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.575, rok: 2021
Způsob publikování: Open access
https://www.mdpi.com/2072-6694/13/7/1709

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.
Trvalý link: http://hdl.handle.net/11104/0319839