Aldehyde stress and up-regulation of Nrf2-mediated antioxidant systems accompany functional adaptations in cardiac mitochondria from mice fed n-3 polyunsaturated fatty acids

摘要

Diets replete with n-3 poly-unsaturated fatty acids (n-3 PUFAs) are known to have therapeutic potential for the heart, although a specifically defined duration of n-3 PUFA diet required to achieve these effects remains unknown, as does their mechanism of action. This study was undertaken to establish whether adaptations in mitochondrial function and stress tolerance in the heart is evident following a short- (3 weeks) and long-term (14 weeks) dietary intervention of n-3 PUFAs, and to identify novel mechanisms by which these adaptations occur. Mitochondrial respiration (mO2), H2O2 emission (mH2O2) and Ca²⁺ retention capacity (mCa²⁺) were assessed in mouse hearts following dietary intervention. Mice fed n-3 PUFA’s for 14 weeks showed significantly lower mH2O2 and greater mCa²⁺ compared to all other groups. However, no significant differences were observed after 3 weeks of n-3 PUFA diet, or in mice fed a high fat diet devoid of n-3 PUFAs for 14 weeks. Interestingly, at 14 weeks n-3 PUFA mice had significantly greater glutathione reductase activity, reflected by a substantially higher GSH/GSSG ratio. Levels of protein adducts of 4-hydroxyhexenal, an aldehyde formed from peroxidation of n-3 PUFAs, were significantly elevated in n-3 PUFA fed mice, even at 3 weeks. These findings demonstrate distinct time-dependent effects of n-3 PUFAs on mitochondrial function and stress tolerance in the heart. In addition, they are first to provide direct evidence that increases in non-enzymatic lipid oxidation products precede these mitochondrial and redox-mediated adaptations, thereby revealing a novel mechanism for n-3 PUFA action in heart.