IDH1 and IDH2 have critical roles in 2-hydroxyglutarate production in D-2-hydroxyglutarate dehydrogenase depleted cells.
D-2-hydroxyglutaric aciduria (D-2HGA) is a hereditary metabolic disorder characterized by the elevated levels of D-2-hydroxyglutaric acid (D-2HG) in urine, plasma and cerebrospinal fluid. About half of the patients have autosomal recessive mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene. To analyze the origin of D-2HG in D2HGDH-depleted cells, we used small interfering RNA (siRNA) techniques. We found that knockdown of D2HGDH in MCF7 cells increased the levels of 2HG, mimicking D2HGDH mutant cells. Additional knockdown of isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) decreased the level of 2HG in D2HGDH knockdown MCF7 cells. Conversely, ectopic expression of IDH1 or IDH2 increased 2HG in MCF7 cells. These results suggest that IDH1 and IDH2 have roles in production of D-2HG in cells.
Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Hironori
H
Matsunaga
Akiko
A
Futakuchi-Tsuchida
Makoto
M
Takahashi
Tomio
T
Ishikawa
Makoto
M
Tsuji
Osamu
O
Ando
D000429:Alcohol Oxidoreductases / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
D005977:Glutarates; D034741:RNA, Small Interfering; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C558760:D2HGDH protein, human