Details

Autor(en) / Beteiligte

• Lambhate, Surbhi
• Bhattacharjee, Debanjan
• Jain, Nishant

Titel

APC/C CDH1 ubiquitinates IDH2 contributing to ROS increase in mitosis

Ist Teil von

• Cellular signalling, 2021-10, Vol.86, p.110087-110087, Article 110087

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Proposed mechanism to show Mito-IDH1 and ubiquitinated IDH2 regulating NADPH and ROS levels in mitosis. [Display omitted] •Wild-type and pathogenic mutants of IDH2 are ubiquitinated by APC/C CDH1 in mitosis.•Ubiquitination of IDH2 contributes to ROS increase in mitosis.•Mito-IDH1 offsets ubiquitinated IDH2.