They account for nearly 83% of all cells in the human body, yet red blood cells are often portrayed as little more than bags of hemoglobin ferrying oxygen from the lungs to the heart and beyond. But new research from the University of Colorado Anschutz reveals that they are vastly more complex with far reaching consequences for health, exercise and fitness.
In a study published today in Blood, scientists identified 3,775 proteins in ultra-pure mature human red blood cells – more than triple the estimates from just 15 years ago - and mapped thousands of physical interactions among them, revealing a surprisingly dynamic network that adapts quickly when oxygen levels fall.
The findings offer new insight into how the body responds to low-oxygen during high-altitude exposure and strenuous exercise, as well as during pathological hypoxia, including the severe loss of oxygen delivery that can occur after trauma and hemorrhagic shock.
“Red blood cells are far more sophisticated than previously thought,” said the study’s senior author Angelo D’Alessandro, PhD, professor of biochemistry and molecular genetics at CU Anschutz. “They have no nucleus and cannot turn genes on or off to make new proteins. Yet every few seconds they move between oxygen-rich and oxygen-poor environments and have to adapt almost instantly. Our study shows that they accomplish this, in part, by continually reorganizing the proteins they already have.”
The center of this oxygen-sensitive network is Band 3, the most abundant protein in the red blood cell membrane. The researchers discovered a previously unknown interaction between Band 3 and biliverdin reductase B, or BLVRB, connecting cell membrane changes to the metabolic machinery within it.
When oxygen levels dropped, nearly one-third of the mapped protein interactions were remodeled. Binding between Band 3 and deoxygenated hemoglobin increased approximately threefold, while glucose metabolism shifted and production of 2,3-BPG increased. This molecule reduces hemoglobin’s grip on oxygen, helping red blood cells release oxygen to tissues that need it most.
The findings may help explain how red blood cells adjust when people travel to or live at high altitude, where oxygen levels are lower.
Red blood cells are known to increase 2,3-BPG during exposure to high altitude, helping compensate for reduced oxygen availability. The new study identifies part of the molecular machinery that may coordinate that response.
To test whether the mechanism mattered in a living organism, the researchers used animal models that lacked the oxygen-responsive N-terminal region of Band 3. Their red blood cells could no longer mount the normal metabolic response to low oxygen, and they showed impaired exercise capacity.
Previous research has shown that red blood cells increase production of 2,3-BPG during high-altitude exposure. The new study identifies a molecular system that may help coordinate that response.
Although the researchers did not directly study athletes or people acclimatizing to high altitude, the findings suggest that the ability of red blood cells to rapidly reorganize their metabolism contributes to the body’s capacity to function when oxygen becomes limiting.
While mature red blood cells have no nucleus and cannot respond to environmental changes by producing new proteins, they can respond by reorganizing and modifying the proteins they already have, the study showed.
“What we are seeing is a cell that adapts without making new proteins,” D’Alessandro said. “Protein interactions become a form of rapid biological regulation.”
The researchers uncovered another layer of this response involving nitric oxide, or NO, which helps regulate blood vessel function. BLVRB acts as a molecular relay, transferring a NO-derived chemical signal to another enzyme that immediately regulates 2,3-BPG synthesis, helping redirect how the cell uses glucose when oxygen levels fall. Remarkably, plants have independently evolved to use essentially the same switch to generate molecules that regulate photosynthesis.
“It is striking to see the same basic chemical strategy used across such distant forms of life,” D’Alessandro said. “In a red blood cell, it helps metabolism respond to changing oxygen. In a plant, it helps redirect carbon toward photosynthesis. Evolution appears to have repeatedly used the same molecular switch to adapt metabolism to changes in the surrounding gases.”
Understanding these mechanisms may help researchers better understand differences in high-altitude adaptation, exercise performance and vulnerability to red blood cell breakdown. It also could provide new insight into blood storage and transfusion.
The researchers have made their detailed red blood cell protein database, called Deep Red, publicly available to help other scientists investigate these mechanisms.
The study brings together researchers from CU Anschutz and collaborating institutions across the United States and Canada. Its significance is also highlighted by an accompanying editorial in Blood and a featured discussion on the American Society of Hematology Podcast.
The study was supported by the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences.
Key Points:
- Red blood cells are far more complex than previously thought: CU Anschutz researchers identified 3,775 proteins in mature human red blood cells — more than three times previous estimates — and mapped thousands of interactions among them.
- They can rapidly adapt to low oxygen without making new proteins: When oxygen levels fall, red blood cells reorganize existing proteins and remodel nearly one-third of their protein interactions, helping shift how they use glucose and release oxygen.
- A newly identified molecular network may help explain adaptation to altitude and exercise: Researchers identified a previously unknown interaction involving Band 3 and BLVRB that helps regulate production of 2,3-BPG, a molecule that enables hemoglobin to release more oxygen to tissues.
- The findings could have implications beyond altitude and fitness: The newly identified mechanisms may help researchers understand exercise capacity, high-altitude adaptation, red blood cell breakdown, trauma and hemorrhagic shock, and blood storage and transfusion.