Oxidative stress underlies the mechanism for Ca2+-induced permeability transition of mitochondria

Tomoko Kanno, Eisuke F. Sato, Shikibu Muranaka, Hirofumi Fujita, Takuzo Fujiwara, Toshihiko Utsumi, Masayasu Inoue, Kozo Utsumi

Research output: Contribution to journalReview article

106 Citations (Scopus)

Abstract

Recent studies demonstrated that the generation of intracellular reactive oxygen species (ROS) was enhanced prior to the onset of mitochondrial membrane permeability transition (MPT), a critical step for the induction of DNA fragmentation and apoptosis. Although Ca2+ induces typical MPT that involves depolarization and swelling of mitochondria and finally releases cytochrome c into cytosol, the mechanism by which ROS induce MPT remains unclear. In the presence of inorganic phosphate, Ca2+ increased the oxygen consumption and ROS production by isolated mitochondria as determined by a chemiluminescence (CHL) method using L-012. Ca2+ increased the generation of H2O2 by some mechanism that was inhibited by cyclosporin A but not by superoxide dismutase (SOD) and trifluoperazine. Ca2+ decreased the content of free thiols in adenine nucleotide translocase (ANT) in mitochondrial membranes with concomitant increase in ROS generation. The presence of cyclosporin A, trifluoperazine, or SOD inhibited the Ca2+-induced increase of L-012 CHL and decrease in the free thiols of ANT. These results indicate that Ca2+ increases the generation of ROS which oxidize the free thiol groups in mitochondrial ANT, thereby inducing MPT to release cytochrome c.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalFree Radical Research
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 1 2004
Externally publishedYes

Keywords

  • Adenine nucleotide translocase
  • Apoptosis
  • Cyclosporin A
  • Membrane permeability transition
  • Protein thiol
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry

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