Hydrogen Peroxide Regulates the Mitochondrial Content of Uncoupling Protein 5 in Colon Cancer Cells

Abstract

Uncoupling protein-2 (UCP2) and uncoupling protein-5 (UCP5) are ion carriers located in the inner mitochondrial membrane that mediate a regulated discharge of the proton gradient generated by the respiratory chain and are possibly involved in the protection against free radical production. Mitochondrial dysfunction is involved in the pathogenesis of colon cancer for which UCP2 has been proposed as a potential therapeutic target. The object of this study was to investigate the possible effects of mitochondrial dysfunction and oxidative stress on the mitochondrial content of UCP2 and UCP5 in colonic cells. Proliferation rate/index, antioxidant systems, reactive oxygen species, oxidative damage, mitochondrial markers and protein expression of UCP2 and UCP5 were analysed in non-metastatic HT-29 cells, metastatic SW-620 cells, and in a HT-29 differentiated derivative (Glu-R). In this study, we found a clear relationship between mitochondrial dysfunction in colonic epithelial cells and the levels of UCP2 and UCP5 proteins. Furthermore, hydrogen peroxide was responsible for the coordinated activation of the antioxidant response and the increase of UCP5 protein levels. Our findings suggest that uncoupling activity could act as a local feedback mechanism to limit the enhanced steady-state H₂O₂ production in dysfunctional mitochondria of colonic cells.