Johns Hopkins researchers have discovered a previously unrecognized role played by the gene HIF-1 as it helps cell survive when a lack of oxygen decreases production of an energy-rich molecule called ATP and increases production of toxic molecules.
ATP supplies energy the cell needs to perform each of its many chemical reactions and tasks, and in this way acts as the "currency" for the cell's energy economy.
A report on the work, done with mouse cells genetically altered to lack the HIF-1 gene, appears in the March 8 issue of Cell Metabolism.
A cell's energy demands are met by two major types of sugar ( glucose) using machines similar to the two types of engines in a hybrid car. One machine, the mitochondrion, is an organelle that breaks down the glucose-using oxygen and produces ATP. The other does the same thing - albeit less efficiently - without using oxygen in a process called glycolysis.
Like the hybrid car, cells use oxygen and the internal combustion engine at higher speeds and rely on an electric engine without need for oxygen consumption at lower speeds. Cells consume glucose through its main energy-producing machine, the mitochondrion, when oxygen is ample. But like the internal combustion engine, this process generates pollutants or toxic oxygen molecules.
At lower oxygen levels, when cells are starved for oxygen - as during exertion or trauma - the genetic switch that the Hopkins researchers found deliberately shuts off the cell's mitochondrial combustion engine, which scientists had long - and erroneously - believed ran down on its own due to lack of oxygen.
"The unexpected discovery is that this genetic switch actively shuts off the mitochondrion under low oxygen conditions, apparently to protect cells from mitochondrial toxic oxygen pollutants," said Chi Van Dang, M.D., Ph.D., professor of medicine, cell biology, oncology and pathology, and vice dean for research at the Johns Hopkins University 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.