Pyruvate dehydrogenase kinases: key regulators of cellular metabolism and therapeutic targets for metabolic diseases.

Abstract

Pyruvate dehydrogenase kinases (PDKs) can regulate the conversion of pyruvate to acetyl coenzyme A through the mitochondrial pyruvate dehydrogenase complex (PDHC). As the rate-limiting enzymes of PDHC, PDKs link glycolysis to the tricarboxylic acid cycle. Pathological changes in many diseases involve alterations in cellular metabolism, which are partly reflected in changes in mitochondrial function. The intermediate role of PDKs in metabolic processes allows for the influence of both glycolysis and oxidative phosphorylation. Recent studies have shown that PDKs play a crucial role in regulating metabolic reprogramming, mitochondrial function and cellular activities in both oncological studies and various non-oncological diseases. This paper aims to clarify the molecular regulatory mechanisms of PDKs; review the relationship of PDKs with cellular metabolic reprogramming, regulation of ROS, and apoptosis; and the present status of research on PDKs in osteoporosis, diabetes mellitus, and vascular diseases. With this review, we have increased our understanding and insight at the molecular level, providing new insights into targeting PDKs to reverse metabolism-related diseases.