PDK4

PDK4, or pyruvate dehydrogenase kinase isozyme 4, is a mitochondrial serine/threonine kinase that phosphorylates the E1 alpha subunit of the pyruvate dehydrogenase complex (PDH). Phosphorylation inhibits PDH activity, decreasing conversion of pyruvate to acetyl-CoA and diverting carbon away from carbohydrate oxidation toward fatty acid oxidation and ketogenesis, thereby shaping cellular energy substrate usage.

PDK4 is one of four PDH kinase isoforms (PDK1–PDK4). It is expressed in multiple tissues, with relatively high levels in skeletal muscle and adipose tissue and variable expression in liver and heart. Its activity and expression are strongly influenced by nutritional and hormonal status, being upregulated during fasting and prolonged energy demand and downregulated in the fed state.

Regulation: PDK4 transcription is induced by fasting, glucocorticoids, and signals that activate PPARα/PPARδ and FOXO transcription factors. It is promoted by high fatty acid availability and energy stress, helping to prioritize lipid oxidation. PDK4 activity is inhibited by pyruvate and, in the context of the PDH phosphatase system, calcium and insulin encourage PDH activation by dephosphorylation.

Clinical and research relevance: Altered PDK4 expression or activity has been linked to impaired glucose oxidation and insulin resistance in metabolic diseases such as type 2 diabetes and obesity. Because PDH activity governs the balance between glucose and lipid utilization, PDK4 is studied as a potential metabolic target, and inhibitors or modulators of PDK4 may influence metabolic flexibility and energy homeostasis.