Nemorosone, a natural-occurring polycyclic polyprenylated acylphloroglucinol, has received increasing attention due to its strong in vitro anti-
cancer action. Here, we have demonstrated the toxic effect of
nemorosone (1-25 μM) on HepG2 cells by means of the MTT assay, as well as early mitochondrial membrane potential dissipation and
ATP depletion in this
cancer cell line. In mitochondria isolated from rat liver,
nemorosone (50-500 nM) displayed a protonophoric uncoupling activity, showing potency comparable to the classic protonophore,
carbonyl cyanide m-chlorophenyl hydrazone (
CCCP).
Nemorosone enhanced the
succinate-supported state 4 respiration rate, dissipated mitochondrial membrane potential, released Ca(2+) from Ca(2+)-loaded mitochondria, decreased Ca(2+) uptake and depleted
ATP. The protonophoric property of
nemorosone was attested by the induction of mitochondrial swelling in hyposmotic K(+)-
acetate medium in the presence of
valinomycin. In addition, uncoupling concentrations of
nemorosone in the presence of Ca(2+) plus
ruthenium red induced the mitochondrial permeability transition process. Therefore,
nemorosone is a new potent protonophoric mitochondrial uncoupler and this property is potentially involved in its toxicity on
cancer cells.