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Neuronal Mitochondrial Toxicity of Malondialdehyde: Inhibitory Effects on Respiratory Function and Enzyme Activities in Rat Brain Mitochondria

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Abstract

Malondialdehyde (MDA) is a product of oxidative damage to lipids, amino acids and DNA, and accumulates with aging and diseases. MDA can possibly react with amines so as to modify proteins and inactivate enzymes; it can also modify nucleosides so as to cause mutagenicity. Brain mitochondrial dysfunction is a major contributor to aging and neurodegenerative diseases. We hypothesize that MDA accumulated during aging targets mitochondrial enzymes so as to cause further mitochondrial dysfunction and additional contributions to aging and neurodegeneration. Herein, we investigated the neuronal mitochondrial toxic effects of MDA on mitochondrial respiration and activities of enzymes (mitochondrial complexes I–V, α-ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase (PDH)), in isolated rat brain mitochondria. MDA depressed mitochondrial membrane potential, and also showed a dose-dependent inhibition of mitochondrial complex I- and complex II-linked respiration. Complex I and II, and PDH activities were depressed by MDA at ≥0.2 μmol/mg; KGDH and complex V were inhibited by ≥0.4 and ≥1.6 μmol MDA/mg, respectively. However, MDA did not have any toxic effects on complex III and IV activities over the range 0–2 μmol/mg. MDA significantly elevated mitochondrial reactive oxygen species (ROS) and protein carbonyls at 0.2 and 0.002 μmol/mg, respectively. As for the antioxidant defense system, a high dose of MDA slightly decreased mitochondrial GSH and superoxide dismutase. These results demonstrate that MDA causes neuronal mitochondrial dysfunction by directly promoting generation of ROS and modifying mitochondrial proteins. The results suggest that MDA-induced neuronal mitochondrial toxicity may be an important contributing factor to brain aging and neurodegenerative diseases.

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Acknowledgments

The authors thank Dr. Edward Sharman for his critical reading and careful editing of this manuscript. This study was supported by an Outstanding Oversea Scholars Award from the Chinese Academy of Sciences, Shanghai Pujiang Talent Award, and a Hi-Sun Science and Technology Prize from Zhejiang Hi-Sun Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Institute for Brain Aging and Dementia, University of California, Irvine, CA, 92697-4540, USA

    Jiangang Long & Jiankang Liu

  2. Institute for Nutritional Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Jiangang Long, Changsheng Liu, Lijuan Sun & Hongxiang Gao

  3. Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    Jiankang Liu

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  1. Jiangang Long
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  2. Changsheng Liu
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Correspondence to Jiankang Liu.

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Special issue article in honor of Dr. Akitane Mori.

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Long, J., Liu, C., Sun, L. et al. Neuronal Mitochondrial Toxicity of Malondialdehyde: Inhibitory Effects on Respiratory Function and Enzyme Activities in Rat Brain Mitochondria. Neurochem Res 34, 786–794 (2009). https://doi.org/10.1007/s11064-008-9882-7

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