Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart

Abstract

Methionine restriction without energy restriction increases, like caloric restriction, maximum longevity in rodents. Previous studies have shown that methionine restriction strongly decreases mitochondrial reactive oxygen species (ROS) production and oxidative damage to mitochondrial DNA, lowers membrane unsaturation, and decreases five different markers of protein oxidation in rat heart and liver mitochondria. It is unknown whether methionine supplementation in the diet can induce opposite changes, which is also interesting because excessive dietary methionine is hepatotoxic and induces cardiovascular alterations. Because the detailed mechanisms of methionine-related hepatotoxicity and cardiovascular toxicity are poorly understood and today many Western human populations consume levels of dietary protein (and thus, methionine) 2-3.3 fold higher than the average adult requirement, in the present experiment we analyze the effect of a methionine supplemented diet on mitochondrial ROS production and oxidative damage in the rat liver and heart mitochondria. In this investigation male Wistar rats were fed either a L-methionine-supplemented (2.5 g/100 g) diet without changing any other dietary components or a control (0.86 g/100 g) diet for 7 weeks. It was found that methionine supplementation increased mitochondrial ROS generation and percent free radical leak in rat liver mitochondria but not in rat heart. In agreement with these data oxidative damage to mitochondrial DNA increased only in rat liver, but no changes were observed in five different markers of protein oxidation in both organs. The content of mitochondrial respiratory chain complexes and AIF (apoptosis inducing factor) did not change after the dietary supplementation while fatty acid unsaturation decreased. Methionine, S-AdenosylMethionine and S-AdenosylHomocysteine concentration increased in both organs in the supplemented group. These results show that methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its hepatotoxicity.

The Mitochondrial Free Radical Theory of Aging

“…On the other hand, excessive intake of dietary methionine is toxic. This toxicity far exceeds that produced by any other amino acid, 61 leading to damage in some vital organs and increases in tissue oxidative stress 62,63 with similar negative effects to those observed in rats fed diets with a high protein content. Chronic and excessive methionine supplementation increases plasma hydroperoxides and low-density lipoprotein cholesterol, 64 induces vascular 65 and kidney damage with tubular hypertrophy, 66 raises iron accumulation and lipid peroxidation, and leads to liver dysfunction, 67 besides other alterations in other organs.…”

Comparative Analysis of Mineral Elements and Essential Amino Acids Compositions in <i>Juglans sigillata<i> and <i>J. regia<i> Walnuts Kernels

“…The mean contents of isoleucine were 30.53 mg/g in J. sigillata and 30.24 mg/g in J. regia. A research showed that methionine supplement in the diet specifically increased mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its hepatotoxicity (Gomez et al, 2009) In all the determined essential amino acids, the mean content of leucine was the highest, corresponding the research by Wu et al (2007).…”

The reaction of methionine with hydroxyl radical: reactive intermediates and methanethiol production

“…It is important to note that Western human populations generally consume levels of Met that are several-fold higher in comparison to dietary requirements (Sanz et al 2006;Gomez et al 2009). The negative effects of Met on lifespan have been strongly related with the unpleasant ability of this amino acid to promote oxidative stress, which is implicated in the mechanism of aging.…”

“…The negative effects of Met on lifespan have been strongly related with the unpleasant ability of this amino acid to promote oxidative stress, which is implicated in the mechanism of aging. Met restriction strongly decreases the production of reactive oxygen species in mitochondria, as well as oxidative damage in proteins, membranes and mitochondrial DNA, while increased supplementation of Met shows just the opposite effects (Orentreich et al 1993;Sanz et al 2006;Gomez et al 2009). However, the mechanisms via which Met acts in such a manner in mammalian cells are not understood.…”