Heme-Containing Globins in Intracellular Function: Myoglobin Regulatory and Protective Roles, Neuroglobins, and Cytoglobins

A revolution is underway in the understanding of the roles of globins in intracellular function. New roles of myoglobin are being documented or hypothesized. In addition, new intracellular globins—not known in the twentieth century—have been discovered.

Based on research using myoglobin knockout mice and other methods, researchers now hypothesize that in cardiac muscle and possibly other types of muscle, myoglobin plays a key role in the regulation of mitochondrial respiration, serves as a defense against reactive oxygen species (see Box 8.1), and helps control mitochondrial substrates. We say more here about just the first of these roles. Nitric oxide (NO) potently inhibits cytochrome oxidase (see Figure 8.3) and in this way serves as a key regulator of the rate of mitochondrial O₂ consumption and ATP synthesis in at least certain muscles (notably cardiac). When O₂ is relatively abundant in a cell, myoglobin becomes oxygenated, forming oxymyoglobin (oxyMb). OxyMb breaks down NO, a process that prevents NO inhibition of cytochrome oxidase, thereby permitting the mitochondria to use O₂ to synthesize ATP when O₂ is available. Conversely, when O₂ is low in abundance in a cell, deoxymyoglobin (deoxyMb) forms. DeoxyMb acts as an enzyme that catalyzes NO synthesis; the NO inhibits cytochrome oxidase and thereby inhibits mitochondrial use of O₂ and ATP synthesis. In these ways, myoglobin is a principal player in regulating mitochondrial function to match the availability of O₂.

In 2000, a heme-containing globin expressed in the brain of humans and mice was discovered (based on genomics research) and named neuroglobin (Ngb). Neuroglobins are now known to occur in most (possibly all) vertebrates. They are intracellular (in cytoplasm) and have been observed (usually at low concentration) in most brain neurons, peripheral neurons, the retina, some endocrine glands (e.g., adrenal), and the sperm-producing tissues of the testicles. The functions of neuroglobins are gradually being elucidated. They bind O₂ reversibly with high affinity (like myoglobins). Their chief function may be to act as O₂ stores for the central nervous system and retina. Animals genetically engineered to overexpress neuroglobins recover from strokes better than controls do, suggesting that the neuroglobin O₂ store helps protect neurons when their external O₂ supply is cut off. Neuroglobins might also function in antioxidant defense (see Box 8.1) or as sensors of metabolic stress. Box Extension 24.4 discusses neuroglobin structure and another recently discovered set of cytoplasmic globins, the cytoglobins.

Neuroglobins resemble single-unit hemoglobins in their molecular structure. They differ, however, in several ways. One is that the heme Fe atom is coordinated with the protein at six positions (instead of five as in hemoglobins). A consequence is that when O₂ binds to the heme group of a neuroglobin, the O₂ must displace another ligand, a part of the globin that is associated with the heme Fe at the sixth coordination position in the deoxygenated-state. These facts account for neuroglobins being called hexacoordinated. Neuroglobins, compared with hemoglobins, also have distinctive cavities in the globin structure.

Shortly after the neuroglobins were first reported, the cytoglobins were discovered. The cytoglobins resemble neuroglobins in many key respects. They are hexacoordinated, single-unit molecules that reversibly bind O₂ with high affinity. Although they sometimes occur in neurons, they are found principally in fibroblasts and related cell types. Their functions are as yet poorly known.