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MUCOSAL BIOLOGY

Synergy between docosahexaenoic acid and butyrate elicits p53-independent apoptosis via mitochondrial Ca²⁺ accumulation in colonocytes

¹Faculty of Nutrition, ²Department of Veterinary Integrative Biosciences, and ³Center for Environmental and Rural Health, ⁴Department of Statistics, Texas A&M University, College Station, Texas

Submitted 11 July 2007 ; accepted in final form 22 August 2007

Butyrate, a short-chain fatty acid fiber fermentation product, induces colonocyte apoptosis in part via a Fas-mediated (extrinsic) pathway. In previous studies, we demonstrated that docosahexaenoic acid (DHA, 22:6^{4,7,10,13,16,19}) enhances the effect of butyrate by increasing mitochondrial lipid oxidation and mitochondrial Ca²⁺-dependent apoptosis in the colon. In this study, we further examined the mechanism of DHA-butyrate synergism in 1) human colon tumor (HCT-116 isogenic p53+/+ vs. p53–/–) cells and 2) primary cultures of rat colonic crypts. Herein, we show that DHA and butyrate promote apoptosis by enhancing mitochondrial Ca²⁺ accumulation in both isogenic cell lines. Ca²⁺ accumulation and apoptosis were inhibited by blockade of mitochondrial uniporter-mediated Ca²⁺ uptake. In addition, Mito-Q, a mitochondria-targeted antioxidant, also blocked apoptosis induced by DHA and butyrate. In complementary experiments, rats were fed diets supplemented with either corn oil (control, contains no DHA) or fish oil (contains DHA). Colonic crypts were isolated and incubated with or without butyrate, after which the mitochondria-to-cytosol Ca²⁺ ratio and crypt viability were measured. No significant difference (P > 0.05) in basal mitochondrial Ca²⁺ levels was observed between fish oil- or corn oil-fed animals. In contrast, when fish oil was the dietary lipid source, crypts incubated with butyrate exhibited a significant increase (3.6-fold, P < 0.001) in mitochondrial Ca²⁺ compared with corn oil plus butyrate treatment. On the basis of these data, we propose that the combination of DHA and butyrate compared with butyrate alone further enhances colonocyte apoptosis by inducing a p53-independent, oxidation-sensitive, mitochondrial Ca²⁺-dependent (intrinsic) pathway.

n-3 polyunsaturated fatty acids; chemoprevention; fish oil; fermentable fiber

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