The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat

Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.

Automated summary

Pyruvate dehydrogenase complexes (PDC) are key components of energy metabolism in all organisms. In eukaryotes, they play a crucial role in connecting glycolysis in the cytoplasm with the tricarboxylic acid cycle in the mitochondria. PDCs also impact the metabolism of amino acids and lipids, as well as oxidative phosphorylation. Its activity is essential for the metabolic and bioenergetic flexibility of organisms in response to developmental changes, nutrient availability, and various stresses.