MECHANISMS INVOLVED IN THE REGULATION OF CELLULAR GLUCOSE METABOLISM

Abstract

Cellular glucose metabolism involves the conversion of glucose into CO2 and H2O via glycolysis and oxidative phosphorylation to produce ATP and into numerous metabolites that are critical for biosynthesis of organic molecules as well as for a number of protein modifications. Cellular glucose metabolism is known to be deregulated in pathological conditions, particularly in cancer and diabetes. HIF-1 and Txnip are two major regulators of cellular glucose metabolism. HIF-1 promotes the glycolytic pathway during hypoxia by upregulating genes encoding glucose transporters and a series of glycolytic enzymes while inhibiting mitochondrial oxidative phosphorylation. Txnip acts as a negative regulator of glucose uptake, thus leading to a decrease in cellular glucose utilization. To gain further insights into the regulation of cellular glucose metabolism, we investigated how HIF-1 alpha is regulated by mitochondrial activity as well as the mechanism through which Txnip regulates cellular glucose uptake. HIF-1alpha protein stabilization is known to be dependent on a functional mitochondrial electron transport chain. It has been suggested that mitochondrial electron transport promotes HIF-1alpha protein stabilization by either decreasing the cellular oxygen availability or by producing and releasing reactive oxygen species that originate from complex III. In our study, we found that ROS production by mitochondrial complex III is not required for hypoxia-induced HIF-1alpha stabilization. This conclusion is based on a number of results. For instance, reestablishing mitochondrial oxygen consumption in the presence of a complex III inhibitor using an artificial electron donor to complex IV or by overexpressing Ciona intestinalis alternative oxidase results in HIF-1alpha protein stabilization in hypoxia. Furthermore, five inhibitors that target different sites of the mitochondrial electron transport chain have similar effects on the HIF-1alpha protein half-life in hypoxia b007500740020007600610072007900200069006E002000740068006500690072002000650066006600650063007400730020006F006E0020006D00690074006F00630068006F006E0064007200690061006C00200052004F0053002000700072006F00640075006300740069006F006E002E002000460069006E0061006C006C0079002C00200052004F005300200064006F0020006E006F007400200072006500670075006C006100740065002000700072006F006C0079006C00200068007900640072006F00780079006C0061007300650020006100630074006900760069007400790020006400690072006500630074006C0079002E0020004F0075007200200072006500730075006C0074007300200073007500670067006500730074002000740068006100740020006D00690074006F00630068006F006E00640072006900610020006D006F00640075006C0061007400650020007400680065002000630065006C006C0075006C006100720020006800790070006F00780069006300200072006500730070006F006E0073006500200062007900200072006500670075006C006100740069006E0067002000630065006C006C0075006C006100720020006F0078007900670065006E00200061007600610069006C006100620069006C006900740079002E000D000A002000200020002000200049006E00200074006800650020007300650063006F006E0064002000700061007200740020006F00660020007400680065002000730074007500640079002C0020007700650020007300740075006400690065006400200074006800650020006D0065006300680061006E00690073006D0020007400680072006F007500670068002000770068006900630068002000740068006500200061006C007000680061002D0061007200720065007300740069006E002000700072006F007400650069006E0073002000540078006E0069007000200061006E0064002000410072007200640063003400200069006E00680069006200690074002000630065006C006C0075006C0061007200200067006C00750063006F007300650020007500740069006C0069007A006100740069006F006E002E00200049007400200068006100730020006200650065006E0020007200650070006F007200740065006400200074006800610074002000540078006E0069007000200072006500670075006C006100740065002000630065006C006C0075006C0061007200200067006C00750063006F007300650020007500740069006C0069007A006100740069006F006E00200069006E006400690072006500630074006C0079002000620079002000700072006F006D006F00740069006E00670020006D00690074006F00630068006F006E0064007200690061006C002000660075006E006300740069006F006E002E00200048006F00770065007600650072002C002000770065002000730068006F00770020007400680061007400200069006E006800690062006900740069006F006E0020006F0066002000630065006C006C0075006C0061007200200067006C00750063006F007300650020007500740069006C0069007A006100740069006F006E002000620079002000540078006E0069007000200061006E0064002000410072007200640063003400200077006100730020007300750073007400610069006E006500640020007700680065006E00200074006800650020006D00690074006F00630068006F006E0064007200690061006C0020004500540043002000770061007300200069006E0068006900620069007400650064002E0020004F0075007200200072006500730075006C0074007300200069006E00640069006300610074006500200074006800610074002000740068006500200061006C007000680061002D0061007200720065007300740069006E002000700072006F007400650069006E007300200063006F006D00700072006F006D00690073006500200067006C00790063006F006C00790074006900630020004100540050002000700072006F00640075006300740069006F006E002E00200057006500200061006C0073006F002000730068006F007700200074006800610074002000540078006E0069007000200061006E0064002000410072007200640063003400200069006E0068006900620069007400200067006C00750063006F0073006500200063006F006E00730075006D007000740069006F006E00200062007500740020006E006F0074002000740068006500200067006C00790063006F006C007900740069006300200063006100730063006100640065002000730069006E00630065002000740068006500200061006C007000680061002D0061007200720065007300740069006E002000700072006F007400650069006E00730020006C006F007700650072006500640020007400680065002000630065006C006C0075006C0061007200200063006F006E00630065006E00740072006100740069006F006E00730020006F0066002000660072007500630074006F00730065002D0032002C0036002D00620069007300700068006F00730070006800610074006500200061006E006400200067006C00750063006F00730065002D0036002D00700068006F00730070006800610074006500200077006900740068006F0075007400200061006600660065006300740069006E0067002000740068006500200065006E007A