Manganese superoxide dismutase, MnSOD and its mimics

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 MitoQ10 in detail, and briefly addresses several other compounds that are either catalysts of O2− dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O2− dismutation, MitoQ10 oxidizes O2− to O2 with a high rate constant. In vivo it is readily reduced to quinol, MitoQH2, which in turn reduces ONOO− to NO2, producing semiquinone radical that subsequently dismutes to MitoQ10 and MitoQH2, completing the “catalytic” cycle. In MitoQ10, 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.

► MnSOD action was briefly summarized and compared to the action of its mimics.
► Mn porphyrins and MitoQ were described in details.
► Cationic Mn(III) N-alkylpyridylporphyrins mimic both the catalytic action and location of MnSOD.
► MitoQ accumulates in mitochondria and scavenges superoxide stoichiometrically.