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Review
. 2018 May 18;293(20):7522-7530.
doi: 10.1074/jbc.TM117.000259. Epub 2017 Nov 30.

Lipoic acid metabolism and mitochondrial redox regulation

Ashley Solmonson  1 , Ralph J DeBerardinis  2
Affiliations
Review

Lipoic acid metabolism and mitochondrial redox regulation

Ashley Solmonson et al. J Biol Chem. .

Abstract

Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty-acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multienzyme complexes. Many of these dehydrogenases are regulated by reactive oxygen species, mediated through the disulfide bond of the prosthetic lipoyl moiety. Collectively, its functions explain why lipoic acid is required for cell growth, mitochondrial activity, and coordination of fuel metabolism.

Keywords: cell metabolism; lipoic acid; mitochondria; oxidation-reduction (redox); redox regulation; tricarboxylic acid cycle (TCA cycle) (Krebs cycle).

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Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Structures, enzymes, and reaction mechanisms of lipoic acid metabolism. A, de novo lipoic acid synthesis and salvage pathways in E. coli. B, lipoic acid metabolic pathway in S. cerevisiae and Homo sapiens. C, orthologous enzymes associated with lipoic acid metabolism in each organism.
Figure 2.
Figure 2.
Reaction mechanisms of mitochondrial 2-ketoacid dehydrogenases and redox-dependent regulation. 2-Ketoacid dehydrogenase complexes consist of three enzyme subunits that use coupled reactions to decarboxylate a 2-ketoacid substrate and produce a CoA ester. The E1 subunit is a 2-ketoacid decarboxylase that uses a covalently bound thymine pyrophosphate (TPP) cofactor to decarboxylate the 2-ketoacid substrate followed by reductive acylation of a lipoyl moiety on the E2 subunit. The E2 subunit is a dihydrolipoamide acyltransferase that transfers the acyl intermediate from the E1 subunit to CoA generating an acyl-CoA and dihydrolipoamide. The E3 subunit is a dihydrolipoamide dehydrogenase that uses FAD to oxidize the lipoyl group on the E2 subunit for subsequent rounds of catalysis and generates NADH through coupled oxidation–reduction reactions of FADH2 and NAD+.
Figure 3.
Figure 3.
Mitochondrial 2-ketoacid dehydrogenases and the TCA cycle. Mitochondrial lipoylated enzymes individually contribute to pathways that generate products that can participate in the TCA cycle. Inborn errors in these dehydrogenases can be deleterious, with clinical symptoms including developmental delay (PDH and BCKDH), encephalopathy (OGDH), and microcephaly (2-OADH). Deficiencies in these enzymes can accumulate metabolites, including pyruvate and lactate (PDH), α-ketoglutarate and 2-hydroxyglutarate, branched-chain amino acids and their corresponding 2-ketoacids, and 2-oxoadipic acid. Deficiencies in lipoic acid metabolism can phenocopy multiple simultaneous 2-ketoacid dehydrogenase deficiencies and can limit the incorporation of carbon into the TCA cycle from various sources.
Figure 4.
Figure 4.
Regulation of OGDH by reversible glutathionylation. A, 2-oxoglutarate dehydrogenase (OGDH) interacts with complex I of the mitochondrial electron transport chain, and both complexes can generate ROS. B, when ROS levels increase, both complexes are glutathionylated, which is thought to dissociate the interaction between the two complexes and reversibly inactivate OGDH. The OGDH complex is protected from oxidative damage by thioredoxin (Trx2), and the glutathionylation is regulated by glutathione reductase (Grx2). Glutathionylation of the lipoyl moiety on the E2 subunit of OGDH may allow for ROS scavenging by the E3 subunit through interactions with Grx2 and Trx2.
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