Endogenous Production of Lipoic Acid Is Essential for Mouse Development

Abstract

α-Lipoic acid (LA) is a cofactor for mitochondrial α-ketoacid dehydrogenase complexes and is one of the most potent, natural antioxidants. Reduction of oxidative stress by LA supplementation has been demonstrated in patients with diabetic neuropathy and in animal models. To determine how normal development or pathological conditions are affected by genetic alterations in the ability of mammalian cells to synthesize LA and whether dietary LA can circumvent its endogenous absence, we have generated mice deficient in lipoic acid synthase (Lias). Mice heterozygous for disruption of the Lias gene develop normally, and their plasma levels of thiobarbituric acid-reactive substances do not differ from those of wild-type mice. However, the heterozygotes have significantly reduced erythrocyte glutathione levels, indicating that their endogenous antioxidant capacity is lower than those of wild-type mice. Homozygous embryos lacking Lias appear healthy at the blastocyst stage, but their development is retarded globally by 7.5 days postcoitum (dpc), and all the null embryos die before 9.5 dpc. Supplementing the diet of heterozygous mothers with LA (1.65 g/kg of body weight) during pregnancy fails to prevent the prenatal deaths of homozygous embryos. Thus, endogenous LA synthesis is essential for developmental survival and cannot be replaced by LA in maternal tissues and blood.

ACKNOWLEDGMENTS

This work was supported by grants (HL42630 and HL70523) from the National Institutes of Health.

We thank Oliver Smithies, Kathleen Caron, Kathleen Sulik, Hyung-Suk Kim, Seigo Hatada, and Nobuyuki Takahashi for valuable advice. We also thank Sylvia Hiller, Angie Ponguta, John Hagaman, Jennifer Wilder, and John Cowhig for expert technical assistance and Raymond Givens and Lance Johnson for helpful comments on the manuscript.