Regulation of pyruvate metabolism and human disease

Abstract

Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health.

Lactic Acidosis in a Patient with Type 2 Diabetes Mellitus

“…One large population-based study has shown an incidence of lactic acidosis of 3% among all patients with diabetes mellitus compared with 0.1% in the nondiabetic population (12). The causes of this predisposition are not known but have been postulated to include a propensity for tissue hypoxia because of large and small vessel disease and alterations in pyruvate metabolism (13). In the absence of another cause, however, diabetes will not result in lactic acidosis of the degree seen in this patient.…”

Diabetic Retinopathy and Laser Therapy in Rats: A Protein-Protein Interaction Network Analysis

“…Pyruvate metabolic process is another detected pathway. Pyruvate is the end-product of glycolysis 78 and its dysmetabolism contributes to failure of the pancreatic islet β-cells during late type 2 diabetes. 79 Its up regulation can lead to excessive fatty acid oxidation and ROS formation in the mitochondria.…”

Vitamin C Increases the Level of Lactate Dehydrogenase in Rats ‘Oral Squamous Cell Carcinoma

“…Its extracellular presence is associated with cell necrosis and tissue breakdown (Gray et al 2014). Since the discovery of LDH and its importance as a marker of tumorigenesis, it has been utilized as a diagnostic enzyme to distinguish between normal, premalignant, and malignant cells (Andreoli & Alpern, 1993).…”