Data from Dietary Fish Oil Promotes Colonic Apoptosis and Mitochondrial Proton Leak in Oxidatively Stressed Mice

Abstract

<div>Abstract<p>An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis <i>in vivo</i>, we fed heterozygous SOD2<sup>Het</sup>, Gpx4<sup>Het</sup>, and transgenic Gpx4<sup>Tg</sup> mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4<sup>Het</sup> > SOD2<sup>Het</sup> > Wt > Gpx4<sup>Tg</sup>), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4<sup>Het</sup> and SOD2<sup>Het</sup> mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4<sup>Tg</sup> mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (<i>P</i> < 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. <i>Cancer Prev Res; 4(8); 1267–74. ©2011 AACR</i>.</p></div>