Endogenous Production of Lipoic Acid Is Essential for Mouse Development

Abstract

␣-Lipoic acid (LA) is a cofactor for mitochondrial ␣-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.R-␣-Lipoic acid (6,8-thioctic acid) (LA) is a crucial cofactor that is required for the activity of the multienzyme complexes involved in the decarboxylation of ␣-ketoacids, important steps in energy metabolism. These complexes include pyruvate dehydrogenase complex (PDC), ␣-ketoglutarate dehydrogenase complex, branched chain ␣-ketoacid dehydrogenase complex (32), and a glycine cleavage system (11). LA is covalently attached via an amide bond to specific lysine residues of the E2 subunits of these complexes. LA is universally present in prokaryotes and eukaryotes (28), and previous investigations have shown that it is synthesized by lipoic acid synthase from octanoic acid and a sulfur source (23,25). Mouse lipoic acid synthase is encoded by the nuclear gene Lias.LA, one of the most potent natural antioxidants, has received considerable attention as a general dietary supplement for the past 15 years (3). Many lines of evidence have shown that both LA and its reduced form, dihydrolipoic acid (DHLA), have multifunctional antioxidant activities with the following characteristics (29). First, LA/DHLA are amphiphilic and readily cross the blood-brain barrier and cell membranes. Second, LA/DHLA possess metal-chelating activity. Third, LA is reduced to DHLA by several antioxidant enzymes that are expressed constitutively in most types of cells. In addition, because of its strong negative redox potential, DHLA can recycle other antioxidants, such as vitamin C, vitamin E, glutathione, coenzyme Q10, and ubiquinone (14,15,21,29,33).A growing body of evidence implicates oxidative stress as an important pathogenic element in a variety of diseases, including atheroscle...

Lipoic Acid Synthase (LASY)

“…Our in vitro data showing that knockdown of LASY results in decreased GSH levels is consistent with published literature. A significant decrease in erythrocyte GSH levels has been reported in mice that are heterozygous for disruption of the LASY gene (12). Accumulation of excessive amounts of ROS such as superoxide anion could directly inflict damage on cellular macromolecules.…”

Reversible Sequestration of Active Site Cysteines in a 2Fe-2S-bridged Dimer Provides a Mechanism for Glutaredoxin 2 Regulation in Human Mitochondria

“…It therefore seems that this tight control of GLRX2 activity, through sequestration into a resting dimeric state and inhibition by GSH, coupled with its intrinsically lower activity, is of major biological importance for mitochondrial homeostasis. Clearly, further experiments are necessary to dissect the role of GLRX2 in mitochondrial redox control and to investigate possible interactions with other mitochondrial thiol scavengers such as lipoic acid, which has also been shown to be involved in mitochondrial redox control (25)(26)(27). Of particular relevance, dihydrolipoamide can supply electrons to GLRX2 (28), indicating a connection between lipoic acid or its derivatives and GLRX2 in redox control.…”

The Mycobacterium tuberculosis LipB enzyme functions as a cysteine/lysine dyad acyltransferase

“…For instance, a Listeria monocytogenes mutant strain lacking LplA has been found to be defective in its ability to grow in the host cytosol and is less virulent in animals because of its dependence on host-derived lipoic acid (8). Mice Lias Ϫ/Ϫ (LipA) null variants die during embryogenesis, indicating that the mammalian pathway is related to the bacterial LipB͞LipA pathway and is essential for life (9). In contrast, in apicomplexan parasites, such as Plasmodium falciparum and Toxoplasma gondii, the two lipoylation pathways appear to be compartmentalized and are found either in mitochondria (LplA) or in the apicoplasts (LipA and LipB) (10,11).…”