In 1992, Semenza's team had discovered a protein which they called HIF-1 (for hypoxia-inducible factor 1) that cells make in response to hypoxia. HIF-1 turns on genes that help cells survive when oxygen is low, such as during a heart attack or stroke. The researchers set out to figure out if the sensor protein HIF-1 triggers the COX-swapping.
By examining the gene control regions of COX4, they found that the HIF-1 sensor switched on COX4-2 activity when oxygen is low. And they learned that because COX4-1 already is in the mitochondria, the swap for COX4-2 occurs when the sensor turns on yet another gene that produces an enzyme to specifically chew up COX4-1. Engineering human cells to lack this enzyme and subjecting them to low oxygen, the scientists found the cells unable to rid themselves of COX4-1.
"It's remarkable that the one-celled yeast also swap COX subunits in response to hypoxia, but because they lack HIF-1, they accomplish the swap in a completely different way," says Semenza. "This suggests that adapting mitochondria to changes in oxygen levels may be a major challenge for most organisms on Earth."