Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death

Hideyuki J. Majima, Terry D. Oberley, Katsutoshi Furukawa, Mark P. Mattson, Hsiu Chuan Yen, Luke I. Szweda, Daret K. St. Clair

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Alkalosis is a clinical complication resulting from various pathological and physiological conditions. Although it is well established that reducing the cellular proton concentration is lethal, the mechanism leading to cell death is unknown. Mitochondrial respiration generates a proton gradient and superoxide radicals, suggesting a possible link between oxidative stress, mitochondrial integrity, and alkaline-induced cell death. Manganese superoxide dismutase removes superoxide radicals in mitochondria, and thus protects mitochondria from oxidative injury. Cells cultured under alkaline conditions were found to exhibit elevated levels of mitochondrial membrane potential, reactive oxygen species, and calcium which was accompanied by mitochondrial damage, DNA fragmentation, and cell death. Overexpression of manganese superoxide dismutase reduced the levels of intracellular reactive oxygen species and calcium, restored mitochondrial transmembrane potential, and prevented cell death. The results suggest that mitochondria are the primary target for alkaline-induced cell death and that free radical generation is an important and early event conveying cell death signals under alkaline conditions.

Original languageEnglish
Pages (from-to)8217-8224
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number14
DOIs
Publication statusPublished - 1998 Apr 3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Majima, H. J., Oberley, T. D., Furukawa, K., Mattson, M. P., Yen, H. C., Szweda, L. I., & St. Clair, D. K. (1998). Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death. Journal of Biological Chemistry, 273(14), 8217-8224. https://doi.org/10.1074/jbc.273.14.8217