Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 26 February 2021 / Approved: 1 March 2021 / Online: 1 March 2021 (13:03:24 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Cancers 2021, 13, 1709
DOI: 10.3390/cancers13071709

Abstract

Mitochondrial production of 2-hydroxyglutarate (R-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 analyzed 2HG levels and its enantiomers in breast cancer cells using analytical approaches for metabolomics. By manipulation of mitochondrial substrate fluxes, including glutaminolysis, using genetic and pharmacological approaches we demonstrated the existence of an active competition between 2HG producing enzymes, i.e. IDH2 and ADHFE1. Moreover, we show 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 into breast cancer patient´s urine 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.

Subject Areas

IDH2; 2HG; breast carcinoma

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