Lipoic acid metabolism and mitochondrial redox regulation

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, alpha-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.

Effects of alpha lipoic acid and its derivative “andrographolid‐lipoic acid‐1” on ulcerative colitis: A systematic review with meta‐analysis of animal studies

“…56 In addition, TNF-α was involved in necroptosis pathway of the intestinal cell death, either through a number of protein kinases that induced membrane depolarization or by induced NF-κB activation. 12 On the contrary, subsequent to trimerization of TNF-α receptor, and recruitment of TNF receptor-associated factor-2 (TRAF-2) and ribosome inactivating protein (RIP) to death domain (DD), both of the TNF receptor type 1-associated DD protein (TRADD), TNF-α R, and IkB kinase (IKKs) were stimulated either directly 58-61 ( Figure 5) or indirectly via MAPK kinase 1-MAPK kinase 4-IKK (MEKK1-MKK4-IKK) pathway, which was stymied by ALA at each stage ( Figure 5). It was evident that the intestinal cell death and homeostasis have been significantly implicated in chronic colitis.…”

“…57 Indeed, ALA interacted with phosphorylation of IkB-α as an NF-κB suppressant within the cytoplasm by means of either mitogen-activated protein kinase (MAPK) or recycling of vitamin E ( Figure 5). 12 On the contrary, subsequent to trimerization of TNF-α receptor, and recruitment of TNF receptor-associated factor-2 (TRAF-2) and ribosome inactivating protein (RIP) to death domain (DD), both of the TNF receptor type 1-associated DD protein (TRADD), TNF-α R, and IkB kinase (IKKs) were stimulated either directly [58][59][60][61] ( Figure 5) or indirectly via MAPK kinase 1-MAPK kinase 4-IKK (MEKK1-MKK4-IKK) pathway, which was stymied by ALA at each stage ( Figure 5). 62,63 On the contrary, it is known that vitamin E, as a protein kinase C (PKC) inhibitor, had contributed to the phosphorylation of IkB.…”

“…10,11 Of note, only R-LA is able to act as a cofactor, since it is conjugated to conserve lysine residues in an amide linkage. 12 ALA directly or indirectly acts against oxidative stress via multiple pathways including free radical elimination, 5,6 metal chelating, inhibition of oxidants generation or reactivity, stimulation of mitochondrial enzymes activity, an increase of antioxidant enzymes expressions, and restoration of antioxidants (vitamin C and E or GSH) or oxidized proteins. LA modulates these multi-enzyme complexes and plays a key role in cell growth and signaling, mitochondrial activity, and metabolism regulation.…”

A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency

“…PDC activity is highly regulated; it is inactivated by phosphorylation of serine sites on E1α by one of four pyruvate dehydrogenase kinases (PDKs: PDK1, PDK2, PDK3, and PDK4), while activation of PDC is achieved by removal of these phosphates from E1α by two pyruvate dehydrogenase phosphatases (PDPs: PDP1 and PDP2) . The lipoate cofactor plays a critical role in stabilizing and regulating PDC function . PDC also is glutathionylated on E2, and this glutathionylation decreases reactive oxygen species (ROS) production when pyruvate is being oxidized, while depletion of glutathione leads to increased ROS production from PDC .…”

“…1 The lipoate cofactor plays a critical role in stabilizing and regulating PDC function. 2 PDC also is glutathionylated on E2, and this glutathionylation decreases reactive oxygen species (ROS) production when pyruvate is being oxidized, while depletion of glutathione leads to increased ROS production from PDC. 3 Glutathione reductase (GRX2) regulates the reversible glutathionylation, which also is important for PDC activity.…”