Manganese superoxide dismutase, MnSOD and its mimics

Sumitra Miriyala, Ivan Spasojevic, Artak Tovmasyan, Daniela Salvemini, Zeljko Vujaskovic, Daret St. Clair, Ines Batinic-Haberle

Research output: Contribution to journalReview articlepeer-review

318 Scopus citations

Abstract

Increased understanding of the role of mitochondria under physiological and pathological conditions parallels increased exploration of synthetic and natural compounds able to mimic MnSOD - endogenous mitochondrial antioxidant defense essential for the existence of virtually all aerobic organisms from bacteria to humans. This review describes most successful mitochondrially-targeted redox-active compounds, Mn porphyrins and MitoQ 10 in detail, and briefly addresses several other compounds that are either catalysts of O 2 - dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O 2 - dismutation, MitoQ 10 oxidizes O 2 - to O 2 with a high rate constant. In vivo it is readily reduced to quinol, MitoQH 2, which in turn reduces ONOO - to NO 2, producing semiquinone radical that subsequently dismutes to MitoQ 10 and MitoQH 2, completing the "catalytic" cycle. In MitoQ 10, the redox-active unit was coupled via 10-carbon atom alkyl chain to monocationic triphenylphosphonium ion in order to reach the mitochondria. Mn porphyrin-based SOD mimics, however, were designed so that their multiple cationic charge and alkyl chains determine both their remarkable SOD potency and carry them into the mitochondria. Several animal efficacy studies such as skin carcinogenesis and UVB-mediated mtDNA damage, and subcellular distribution studies of Saccharomyces cerevisiae and mouse heart provided unambiguous evidence that Mn porphyrins mimic the site and action of MnSOD, which in turn contributes to their efficacy in numerous in vitro and in vivo models of oxidative stress. Within a class of Mn porphyrins, lipophilic analogs are particularly effective for treating central nervous system injuries where mitochondria play key role. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

Original languageEnglish
Pages (from-to)794-814
Number of pages21
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1822
Issue number5
DOIs
StatePublished - May 2012

Bibliographical note

Funding Information:
We acknowledge the support of IBH general research funds Duke University's CTSA grant 1 UL 1 RR024128-01 from NCRR/NIH (AT, IBH, IS), NIH U19AI067798 (ZV, IBH and AT), R01 DA024074 (DS and IBH), and R01 CA 139843 (SM and DKS). Authors are thankful to Irwin Fridovich for critical reading.

Keywords

  • MitoQ
  • Mn porphyrins
  • MnSOD
  • MnSOD mimics
  • MnTE-2-PyP
  • MnTnHex-2-PyP

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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