Oxygen Starved

Hypoxia is the low oxygen environment of tissue lacking blood vessels. Oxygen is needed as the final, low energy electron acceptor of the aerobic metabolism of mitochondria, but it is also needed to make hydroxyproline, the special amino acid of collagen. Expression of genes in response to the oxygen available is controlled by a transcription factor, HIF.

The oxygen that we breathe is used as a place to dump the low energy electrons produced by mitochondria as ATP is using energy from high energy electrons of carbon and hydrogen present initially in glucose. In the absence of oxygen, fermentation can use glycolysis and dispose of the low energy electrons in the form of products such as lactic acid or ethanol. Aerobic metabolism, in the presence of oxygen, is much more efficient (more ATP per glucose), so fermentation is only used when oxygen is depleted, as in the case of exhausted muscles.

Low oxygen, hypoxia, is also encountered in tissues isolated from the oxygen-distributing vascular system. Cells that constantly secrete new cartilage, chondrocytes, are prevented from ready access to oxygen, because the tensile strength of cartilage would be sacrificed by mechanically weak blood vessels. This is paradoxical, because cartilage also contains large amounts of reinforcing collagen fibers, that require oxygen. Consumption of oxygen by aerobic metabolism must be restricted in chondrocytes to reserve diffusing oxygen for collagen synthesis. This also predicts that energy metabolism in chondrocytes exposed to ample oxygen, as in developing bone or wounds, must be drastically different from metabolism in mature chondrocytes that may be centimeters away from the nearest blood vessel.

Oxygen is used in collagen production to produce the hydroxyproline of the repeated triplets of amino acids that form the spiral threads of collagen. Every third amino acid is glycine and prolines that precede a glycine are converted to hydroxyproline by an enzyme that uses vitamin C. Thus, scurvy, a vitamin C deficiency, is characterized by weakened cartilage, e.g. loose teeth. The high hydroxyproline content of collagen also explains the low nutrition of gelatin, which is denatured collagen.

The trigger for shifting a cell to a low oxygen metabolism, is production of hydroxyproline in the transcription factor called, hypoxia-inducible factor, HIF. If oxygen is abundant, a particular proline in HIF is converted to hydroxyproline, and this modified HIF is quickly degraded in proteosomes. Lack of oxygen prevents modification of hydroxyproline and HIF successfully migrates to the nucleus, binds to the promoter sites of specific genes and changes the pattern of proteins in the cell.

HIF is important in all diseases that result in damage to blood supply. Tumors, for example stop growing when they reach a size that limits the oxygen that can diffuse from surrounding blood vessels to the center of the tumor. Hypoxia in a tumor causes release of angiogenic, blood vessel proliferating, cytokines from the tumor. HIF induces the production of angiogenic molecules. In the opposite direction, damage to cartilage that results in increased oxygen, will turn off HIF and prevent the secretion of mature cartilage by chondrocytes. Chondrocytes also secrete proteins that actively block the formation of blood vessels, e.g. endostatin, the end of one of the collagen.

Several drugs are now being developed to block HIF activity and starve cancers. These drugs will also modify the metabolism of many other cells that use HIF. It is worth noting that mice with the HIF gene knocked out do not survive long after birth.