Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia-Reperfusion Injury.
Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia-Reperfusion Injury.
Trends Endocrinol Metab. 2019 Jul;30(7):419-431
Authors: Rabbani N, Thornalley PJ
Abstract
Hexokinase-2 (HK2) was recently found to produce increased metabolic flux through glycolysis in hyperglycemia without concurrent transcriptional or other functional regulation. Rather, stabilization to proteolysis by increased glucose substrate binding produced unscheduled increased glucose metabolism in response to high cytosolic glucose concentration. This produces abnormal increases in glycolytic intermediates or glycolytic overload, driving cell dysfunction and vulnerability to the damaging effects of hyperglycemia in diabetes, explaining tissue-specific pathogenesis. Glycolytic overload is also activated in ischemia-reperfusion injury and cell senescence. A further key feature is HK2 displacement from mitochondria by increased glucose-6-phosphate concentration, inducing mitochondrial dysfunction and oxidative stress. This pathogenic mechanism suggested new targets for therapeutics development that gave promising outcomes in initial clinical evaluation.
PMID: 31221272 [PubMed - in process]
Source: Trends in Endocrinology and Metabolism: TEM - Category: Endocrinology Authors: Rabbani N, Thornalley PJ Tags: Trends Endocrinol Metab Source Type: research