期刊
CELLULAR SIGNALLING
卷 86, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2021.110087
关键词
IDH2; APC; C; CDH1; NADPH; ROS; Mitosis
类别
资金
- Department of Biotechnology, India [6242-P69/RGCB/PMD/DBT/NDJN/2015]
- Council of Scientific and Industrial Research, India [CSIR-IICT/MLP0068]
- Lady Tata Memorial Trust
- CSIR-IICT [IICT/Pubs./2021/066]
Research suggests that ROS progressively increases during mitosis, and IDH2 ubiquitination is linked to ROS production during mitosis, with APC/C CDH1 playing a regulatory role.
NADPH is a cofactor used by reactive oxygen species (ROS) scavenging enzymes to block ROS produced in cells. Recently, it was shown that in cancer cells, ROS progressively increases in tune to cell cycle leading to a peak in mitosis. Loss of IDH2 is known to cause severe oxidative stress in cell and mouse models as ROS increases in mitochondria. Therefore, we hypothesized that IDH2, a major NADPH-producing enzyme in mitochondria is ubiquitinated for ROS to increase in mitosis. To test this hypothesis, in cancer cells we examined IDH2 ubiquitination in mitosis and measured the ROS produced. We found that IDH2 is ubiquitinated in mitosis and on inhibiting anaphase-promoting complex/Cyclosome (APC/C) IDH2 was stabilized. Further, we observed that overexpressing APC/C coactivator CDH1 decreased IDH2, whereas depleting CDH1 decreased IDH2 ubiquitination. To understand the link between IDH2 ubiquitination and ROS produced in mitosis, we show that overexpressing mitochondria-targeted-IDH1 decreased ROS by increasing NADPH in IDH2 ubiquitinated cells. We conclude that APC/C CDH1 ubiquitinates IDH2, a major NADPH-producing enzyme in mitochondria contributing to ROS increase in mitosis. Based on our results, we suggest that mitosis can be a therapeutic window in mutant IDH2-linked pathologies.
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