title: Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission.
abstract: The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses. Sulforaphane (SFN), an electrophilic isothiocyanate derived from cruciferous vegetables, activates the KEAP1-Nrf2-ARE pathway and has become a molecule-of-interest in the treatment of diseases in which chronic oxidative stress plays a major etiological role. We demonstrate here that the mitochondria of cultured, human retinal pigment epithelial (RPE-1) cells treated with SFN undergo hyperfusion that is independent of both Nrf2 and its cytoplasmic inhibitor KEAP1. Mitochondrial fusion has been reported to be cytoprotective by inhibiting pore formation in mitochondria during apoptosis, and consistent with this, we show Nrf2-independent, cytoprotection of SFN-treated cells exposed to the apoptosis-inducer, staurosporine. Mechanistically, SFN mitigates the recruitment and/or retention of the soluble fission factor Drp1 to mitochondria and to peroxisomes but does not affect overall Drp1 abundance. These data demonstrate that the beneficial properties of SFN extend beyond activation of the KEAP1-Nrf2-ARE system and warrant further interrogation given the current use of this agent in multiple clinical trials.
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.
authors.forename: Gary B
authors.initials: GB
authors.lastname: O'Mealey
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Berry
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States. Electronic address: plafkers@omrf.org.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Plafker
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D034281:Dynamins / Q000235:genetics; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D063154:Mitochondrial Dynamics / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides
chemical_list: D000975:Antioxidants; D017879:Isothiocyanates; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013454:Sulfoxides; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D034281:Dynamins; C016766:sulforaphane
keywords: Apoptosis; Drp1; Fission; Fusion; Mitochondria; Nrf2; Sulforaphane