Pyruvate dehydrogenase complex component B: A Gene Associated with Cuproptosis and Encoding the Beta Subunit of Pyruvate Dehydrogenase Is Involved in the Oxidative Decarboxylation Reaction

Abstract

Cuproptosis is a regulated cell death mechanism that has recently been identified and is distinct from other known cell death mechanisms (e.g., apoptosis, Ferroptosis, necrotic apoptosis, etc.). Cuproptosis causes oligomer formation through the abnormal accumulation of intracellular copper ions that target binding to lipocytosed proteins, especially those involved in the tricarboxylic acid cycle. At the same time, it can destabilize iron-containing sulfur proteins, thereby inducing proteotoxic stress, leading to triggered cell death. It has also been shown that cuproptosis is also associated with oxidative stress activation and inhibition of the ubiquitin-proteasome system. Genes linked to cuproptosis were screened, and knocking out seven genes reversed cuproptosis: reductase—ferredoxin 1; the three genes of the lipoic acid pathway—lipoyltransferase 1, lipoyl synthase, and dihydrolipoamide dehydrogenase; and the acylated protein targets—dihydrolipoyl transacetylase (DLAT), pyruvate dehydrogenase complex component A1 (PDHA1), and pyruvate dehydrogenase complex component B (PDHB). Among them, the β subunit of pyruvate dehydrogenase, encoded by the PDHB gene, can form a tetramer with the α subunit and irreversibly catalyze the physiological function of converting pyruvate to acetyl-CoA since DLAT provides structural support and also exhibits enzymatic activity within the pyruvate dehydrogenase complex (PDC). Furthermore, within the PDC, the primary target of cuproptosis is DLAT rather than PDHB or PDHA1. Consequently, the involvement of PDHB in the inactivation of PDC caused by cuproptosis is more likely a secondary consequence. In this review, the characteristics of the cuproptosis-associated gene PDHB and its role in the biological function and pathogenesis of the disease are discussed.