Researchers at Johns Hopkins have discovered how cells
fine-tune their oxygen use to make do with whatever amount
is available at the moment.
Too little oxygen threatens life by compromising
mitochondria that power it, so when oxygen is scarce, cells
appear to adjust by replacing one protein with an
energy-efficient substitute that "is specialized to keep
the motor running smoothly even as it begins to run out of
gas," said Gregg Semenza, a professor of
pediatrics and director of the vascular biology program
in the Institute for
Cell Engineering at Johns Hopkins. "This is one way
that cells maintain energy production under less-than-ideal
conditions." A report on the work is in the April 6 issue
"Cells require a constant supply of oxygen," Semenza
said, "so it's vital for them to quickly react to slight
changes in oxygen levels." The protein swap is how they do
In the mitochondria, the tiny powerhouses found in
every cell, energy is produced by passing electrons through
a series of relay stations called cytochromes until they
eventually join with oxygen to form water.
This final step is directed by the protein cytochrome
c oxidase, or COX for short. If electrons react with oxygen
before reaching COX, they generate "free radicals" that can
damage or destroy cells. The mitochondria are designed to
produce energy without excess free radical production at
normal oxygen levels.
Semenza's team noticed that one particular component
of the COX protein complex, COX4, comes in two different
forms, COX4-1 and COX4-2. Under normal oxygen conditions,
the cells' mitochondria contain mostly COX4-1. The
researchers suspected that COX 4-2 might be the active
protein under stressful low-oxygen conditions, which the
researchers refer to as hypoxia.
To test the idea, the team compared the growth of
human cells in normal oxygen conditions (what's generally
present in normal room air) compared to cells grown in
hypoxia. In low oxygen, liver, uterus, lung and colon cells
all made COX4-2. The researchers then exposed mice to
hypoxia for a few weeks and found that they, too, showed
increased levels of COX4-2.
In 1992, Semenza's team had discovered a protein 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," Semenza said. "This suggests that adapting
mitochondria to changes in oxygen levels may be a major
challenge for most organisms on Earth."
The research was funded by the National Institutes of
Authors on the paper are Ryo Fukuda, Huafeng Zhang,
Jung-whan Kim, Larissa Shimoda, Chi V. Dang and Semenza,
all of Johns Hopkins.