Novel dicarbonyl metabolic pathway via mitochondrial ES1 possessing glyoxalase III activity
Ginga Ito,
Yota Tatara,
Ken Itoh,
Miwa Yamada,
Tetsuro Yamashita,
Kimitoshi Sakamoto,
Takayuki Nozaki,
Kinji Ishida,
Yui Wake,
Takehito Kaneko,
Tomokazu Fukuda,
Eriko Sugano,
Hiroshi Tomita,
Taku Ozaki
Affiliations
Ginga Ito
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Yota Tatara
Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifuchou, Hirosaki, Aomori 036-8562, Japan
Ken Itoh
Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifuchou, Hirosaki, Aomori 036-8562, Japan
Miwa Yamada
Department of Biological Chemistry, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan
Tetsuro Yamashita
Department of Biological Chemistry, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan
Kimitoshi Sakamoto
Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Aomori 036-8561, Japan
Takayuki Nozaki
Technical Support Center for Life Science Research, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate 028-3694, Japan
Kinji Ishida
Technical Support Center for Life Science Research, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate 028-3694, Japan
Yui Wake
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Takehito Kaneko
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Tomokazu Fukuda
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Eriko Sugano
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Hiroshi Tomita
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Taku Ozaki
Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan; Corresponding author at: Laboratory of Cell Biochemistry, Department of Biological Science, Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka Iwate 020-8551, Japan.
Glycation, caused by reactive dicarbonyls, plays a role in various diseases by forming advanced glycation end products. In live cells, reactive dicarbonyls such as glyoxal (GO) and methylglyoxal (MGO) are produced during cell metabolism, and these should be removed consistently. However, the dicarbonyl metabolic system in the mitochondria remains unclear. It has been speculated that the mammalian mitochondrial protein ES1 is a homolog of bacterial elbB possessing glyoxalase III (GLO3) activity. Therefore, in this study, to investigate ES1 functions and GLO3 activity, we generated ES1-knockout (KO) mice and recombinant mouse ES1 protein and investigated the biochemical and histological analyses. In the mitochondrial fraction obtained from ES1-KO mouse brains, the GO metabolism and cytochrome c oxidase activity were significantly lower than those in the mitochondrial fraction obtained from wildtype (WT) mouse brains. However, the morphological features of the mitochondria did not change noticeably in the ES1-KO mouse brains compared with those in the WT mouse brains. The mitochondrial proteome analysis showed that the MGO degradation III pathway and oxidative phosphorylation-related proteins were increased. These should be the response to the reduced GO metabolism caused by ES1 deletion to compensate for the dicarbonyl metabolism and damaged cytochrome c oxidase by elevated GO. Recombinant mouse ES1 protein exhibited catalytic activity of converting GO to glycolic acid. These results indicate that ES1 possesses GLO3 activity and modulates the metabolism of GO in the mitochondria. To our knowledge, this is the first study to show a novel metabolic pathway for reactive dicarbonyls in mitochondria.
