Pyruvate Dehydrogenase Complex Deficiency and Metabolic Regulation
Summary
Pyruvate dehydrogenase complex (PDC) deficiency is a mitochondrial disorder arising from loss-of-function alterations in the multienzyme assembly that converts glycolytic pyruvate into acetyl-CoA, the entry point for the tricarboxylic acid cycle. The resulting bioenergetic shortfall and accumulation of lactate underlie a spectrum of clinical manifestations, most prominently neurodevelopmental delay, lactic acidosis and variable organ involvement. Mutations in the X-linked PDHA1 gene predominate, but variants in other PDC subunit genes and regulatory factors also contribute to heterogeneous presentations. Beyond genetic aetiology, PDC activity is modulated by phosphorylation, allosteric effectors and proteostatic control, while systemic metabolism adapts through compensatory pathways such as glutaminolysis or ketogenesis. Therapeutic strategies have ranged from ketogenic dietary regimens to small-molecule activators of PDC, reflecting an expanding understanding of how modulating flux through this metabolic node can alleviate energy deficits. Recent insights into post-translational mechanisms and non-canonical roles of PDC in nuclear acetyl-CoA provision further highlight its central importance in metabolic regulation across health and disease.
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Pyruvate Dehydrogenase Complex Deficiency and Metabolic Regulation publication trend
The graph below shows the total number of articles in pyruvate dehydrogenase complex deficiency and metabolic regulation across all publications each year (not limited to Nature Index journals).
Technical terms
Pyruvate dehydrogenase complex (PDC): A mitochondrial multienzyme assembly that oxidatively decarboxylates pyruvate to acetyl-CoA, linking glycolysis to the tricarboxylic acid cycle.
Acetyl-CoA: A central metabolite donating acetyl groups for energy production in the tricarboxylic acid cycle and for synthesising lipids and acetylated biomolecules.
Ketogenic diet: A high-fat, low-carbohydrate diet that promotes hepatic ketone body production to supply alternative fuel to glucose-dependent tissues.
Ubiquitination: A post-translational modification in which ubiquitin is covalently attached to target proteins, commonly marking them for proteasomal degradation.
Lactate/pyruvate ratio: A biochemical indicator of the cytosolic redox state and PDC function, with elevated ratios reflecting impaired pyruvate oxidation.
References
- Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients. Orphanet Journal of Rare Diseases (2020).
- Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency—Results from a nationwide population‐based study. Journal of Inherited Metabolic Disease (2021).
- Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1. Biochemistry (2023).
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