title: Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice.
abstract: 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 in vivo, we fed heterozygous SOD2(Het), Gpx4(Het), and transgenic Gpx4(Tg) 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(Het) > SOD2(Het) > Wt > Gpx4(Tg)), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4(Het) and SOD2(Het) mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4(Tg) 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 (P < 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.
authors.affiliation: Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX, USA.
authors.forename: Yang-Yi
authors.initials: YY
authors.lastname: Fan
authors.forename: Qitao
authors.initials: Q
authors.lastname: Ran
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Evelyn S
authors.initials: ES
authors.lastname: Callaway
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Lupton
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002308:Cardiolipins / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003433:Crosses, Genetic; D004042:Dietary Fats, Unsaturated / Q000378:metabolism*; D005395:Fish Oils / Q000378:metabolism*; D005838:Genotype; D005979:Glutathione Peroxidase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D011522:Protons
chemical_list: D002308:Cardiolipins; D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D011522:Protons; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase