Sulforaphane inhibits mitochondrial permeability transition and oxidative stress

Abstract

Exposure of mitochondria to oxidative stress and elevated Ca2+ 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 40 hr later. Respiring mitochondria actively accumulated added Ca2+, which was then released through PTP opening induced by agents that either cause an oxidized shift in the mitochondrial redox state or that directly oxidize protein thiol groups. SFP treatment of rats inhibited the rate of pro-oxidant-induced mitochondrial Ca2+ 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.

Sulforaphane protects against sodium valproate–induced acute liver injury

“…In association, oxidative stress has been reported to contribute significantly to pathophysiology of liver injury (Greco et al 2011).…”

“…Mitochondria have been reported to be a primary target of oxidative stress (Greco et al 2011). Evidence suggests that within mitochondria, ROS and their derivatives initiate oxidative injury of membranous proteins.…”

“…Increased mitochondrial oxidative stress, in turn, induces opening of the mitochondrial permeability transition pore (PTP) (Takeyama et al 1993) D r a f t incapacitating mitochondrial ATP formation, leading to metabolic failure, oncosis and apoptosis (Greco et al 2011;Lee et al 2001). …”

Novel Mitochondrial Targets for Neuroprotection

“…Mitochondria isolated from the livers of rats injected intraperitoneally 40 hours earlier with sulforaphane exhibit elevated immunoreactive levels of glutathione peroxidase 1, thioredoxin 2, and mitochondrial malic enzyme (Greco et al, 2011). These mitochondria are characterized by elevated peroxidase enzyme activity, increased glutathione, and resistance to NAD(P)H oxidation induced by exposure to peroxides.…”

Epigenetic linkage of aging, cancer and nutrition

“…Lastly, SFN induced the hyperacetylation of the TERT promoter and allowed the binding of repressor proteins such as MAD1 (Meeran et al, 2010). Aging is often linked to oxidative stresses; however, SFN has been shown to activate the Nrf2 pathway and increase the expression of antioxidant genes, associating SFN not only with cancer prevention but also with aging (Greco et al, 2011).…”