Sulforaphane Inhibits Mitochondrial Permeability Transition and Oxidative Stress

Free Radic Biol Med. 2011 Dec 15;51(12):2164-71. doi: 10.1016/j.freeradbiomed.2011.09.017. Epub 2011 Sep 21.

Abstract

Exposure of mitochondria to oxidative stress and elevated Ca(2+) promotes opening of the mitochondrial permeability transition pore (PTP), resulting in membrane depolarization, uncoupling of oxidative phosphorylation, and potentially cell death. This study tested the hypothesis that treatment of rats with sulforaphane (SFP), an activator of the Nrf2 pathway of antioxidant gene expression, increases the resistance of liver mitochondria to redox-regulated PTP opening and elevates mitochondrial levels of antioxidants. Rats were injected with SFP or drug vehicle and liver mitochondria were isolated 40h later. Respiring mitochondria actively accumulated added Ca(2+), which was then released through PTP opening induced by agents that either cause an oxidized shift in the mitochondrial redox state or directly oxidize protein thiol groups. SFP treatment of rats inhibited the rate of pro-oxidant-induced mitochondrial Ca(2+) release and increased expression of the glutathione peroxidase/reductase system, thioredoxin, and malic enzyme. These results are the first to demonstrate that SFP treatment of animals increases liver mitochondrial antioxidant defenses and inhibits redox-sensitive PTP opening. This novel form of preconditioning could protect against a variety of pathologies that include oxidative stress and mitochondrial dysfunction in their etiologies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Isothiocyanates
  • Male
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / drug effects*
  • Pyridines / metabolism
  • Rats
  • Rats, Inbred F344
  • Structure-Activity Relationship
  • Thiocyanates / administration & dosage
  • Thiocyanates / pharmacology*

Substances

  • Isothiocyanates
  • Mitochondrial Membrane Transport Proteins
  • Pyridines
  • Thiocyanates
  • mitochondrial permeability transition pore
  • sulforafan
  • Calcium