Celeste Simon studies cellular responses to oxygen deprivation.

Research on how cells respond to low oxygen, or hypoxia, took off in 1995, when a transcription factor named hypoxia-inducible factor, or HIF, was isolated and later shown to activate blood vessel formation and make cancer more aggressive. When Simon began her studies, a key question needed answering: What signals cause HIF to accumulate when oxygen levels drop? Some researchers theorized that HIF directly sensed oxygen, but Simon and others decided to look to mitochondria for signals. The first clue came when her research team suppressed mitochondrial metabolism in a cell culture and found that HIF no longer accumulated during hypoxia.

Now, after a series of experiments, Simon's group has strong evidence that metabolic by-products generated inside mitochondria called reactive oxygen species, or ROS, serve as important signals that stabilize HIF during hypoxia. The team reported its most recent findings in Cell Metabolism in June 2005.

For these studies, Simon's team developed a tool to measure extremely small changes in ROS in real time under the microscope. With this probe, they showed that ROS are produced in larger amounts in mitochondria during hypoxia. Next, the team tinkered with the cells to suppress the amount of ROS they could produce—first by knocking out an important gene and then by adding an enzyme that specifically scavenges ROS. In both cases, without ROS the cells could not launch the normal response to low oxygen. These results suggest that ROS is a necessary signal to cause HIF accumulation during hypoxia.

Photo: William Vazquez

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