Lipoylated tricarboxylic acid cycle enzymes

Lipoylated tricarboxylic acid (TCA) cycle enzymes are a group of mitochondrial multi-enzyme complexes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), that require the covalent attachment of lipoic acid for catalytic function (UniProt, 2024). These enzymes play a central role in cellular respiration by facilitating the conversion of metabolic intermediates into energy (Tsvetkov et al., 2022). The lipoylation process is regulated by the protein ferredoxin 1 (FDX1), which acts as a master regulator of this post-translational modification (Science, 2022). Recent research has identified these lipoylated enzymes as the key mediators of cuproptosis, a copper-dependent form of regulated cell death (Nature Chemical Biology, 2022). In this process, copper ionophores like elesclomol transport copper into the mitochondria, where the metal binds directly to the lipoylated components (PubChem, 2024). This binding leads to protein aggregation, loss of iron-sulfur cluster proteins, and severe proteotoxic stress, ultimately resulting in cell death (Frontiers in Oncology, 2022). This pathway is a promising therapeutic target in oncology, as many cancer cells exhibit increased mitochondrial metabolism and heightened sensitivity to copper-induced proteotoxicity compared to normal cells (Tsvetkov et al., 2022).

Other names

Lipoamide-containing enzymesAlpha-keto acid dehydrogenase complexesLipoylated mitochondrial enzymesCuproptosis targets

Induction of cuproptosis via copper-dependent aggregation of lipoylated enzymes, leading to proteotoxic stress and inhibition of the tricarboxylic acid cycle.