y School of Medicine.
Dang says the switch may be a target for cancer drugs because a cancer cell's survival depends on it to convert glucose to lactic acid through glycolysis even in the presence of ample oxygen. Disruption of the switch by a drug may cause cancer cells to pollute themselves with toxic oxygen molecules and undergo apoptosis or cell death.
The new finding, made by Hopkins graduate student Jung-whan Kim and the Hopkins team led by Dang, showed that during oxygen deprivation, or hypoxia, the HIF-1 gene cuts the link between two ATP-making biochemical pathways: glycolysis, which makes modest amounts of ATP by breaking down the glucose without using oxygen; and the TCA cycle in the mitochondrion, which normally uses oxygen to produce large amounts of ATP by processing a byproduct of glycolysis.
The disruption of this link blocks the tendency of the mitochondrion to make toxic molecules as it struggles to produce ATP during hypoxia. These toxic molecules, called reactive oxygen species (ROS), damage molecules in the cell and even cause the cell to undergo apoptosis.
The target of HIF-1 is the conversion of pyruvate-the byproduct of glycolysis-into another molecule called acetyl co-enzyme A (acetyl CoA), according to Dang. When oxygen levels are normal, the cell produces acetyl CoA and feeds it into the TCA cycle within the mitochondrion. The mitochondrion then processes acetyl CoA using oxygen to obtain large amounts of ATP.
It was already known that during hypoxia, HIF-1 accelerates the output of ATP by glycolysis, Dang noted. But until now researchers thought that HIF-1 simply turned up glycolysis and let the mitochondrion slow down on its own and produce less ATP, he said. Because the mitochondrion runs on oxygen, it doesn't work properly in hypoxic conditions, Dang explained. Instead, glycolysis is left to shoulder the burden of making ATP by being prodded into overdrive by HIF-1. And left to itself during
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Source:Johns Hopkins Medical Institutions
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