Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process

Jun Du, Haruhiko Suzuki, Fumihiko Nagase, Anwarul A. Akhand, Xiu Yang Ma, Toshihiro Yokoyama, Toshio Miyata, Izumi Nakashima

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117 Citations (Scopus)


Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O2-) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O2- is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.

Original languageEnglish
Pages (from-to)469-478
Number of pages10
JournalFree Radical Biology and Medicine
Issue number4
Publication statusPublished - 2001 Aug 15


  • ASK1
  • Apoptosis
  • Free radicals
  • Methylglyoxal
  • Reactive oxygen species
  • Signal transduction
  • Superoxide


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