Switch of Mitochondrial Superoxide Dismutase into a Prooxidant Peroxidase in Manganese-Deficient Cells and Mice

Douglas Ganini*, Janine H. Santos, Marcelo G. Bonini, Ronald P. Mason

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Superoxide radical anion (O 2 ⋅‒ ) and other reactive oxygen species are constantly produced during respiration. In mitochondria, the dismutation of O 2 ⋅‒ is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. Here we show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H 2 O 2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells and in vivo. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells and in vivo. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases. Ganini et al. demonstrate that incorporation of iron over manganese by the mitochondrial superoxide dismutase (SOD2) generates a prooxidant peroxidase in mitochondria of human cells and mice. They show that FeSOD2 formation leads to mitochondrial dysfunction and oxidative stress.

Original languageEnglish (US)
Pages (from-to)413-425.e6
JournalCell Chemical Biology
Volume25
Issue number4
DOIs
StatePublished - Apr 19 2018
Externally publishedYes

Keywords

  • SOD2
  • free radicals
  • iron
  • manganese
  • metals
  • mitochondria
  • mitochondrial ROS
  • mitochondrial metabolism
  • mitochondrial superoxide dismutase
  • oxidative stress
  • peroxidase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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