Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission

Redox Biol. 2017 Apr;11:103-110. doi: 10.1016/j.redox.2016.11.007. Epub 2016 Nov 21.

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.

Keywords: Apoptosis; Drp1; Fission; Fusion; Mitochondria; Nrf2; Sulforaphane.

MeSH terms

  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Carboxylic Ester Hydrolases / genetics*
  • Dynamins / genetics
  • Humans
  • Isothiocyanates / pharmacology
  • Kelch-Like ECH-Associated Protein 1 / genetics*
  • Mitochondria / drug effects
  • Mitochondria / genetics*
  • Mitochondrial Dynamics / genetics
  • NF-E2-Related Factor 2 / genetics*
  • Oxidative Stress / drug effects
  • Retinal Pigment Epithelium / metabolism
  • Signal Transduction / drug effects

Substances

  • Antioxidants
  • Isothiocyanates
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Carboxylic Ester Hydrolases
  • arylesterase
  • Dynamins
  • sulforaphane