Structural Biochemistry/Neuroglobin

Overview
Neuroglobin is a recently discovered member of the globin family. Only discovered in 2000, this protein's function is not entirely certain, but there are many hypotheses that define its use. Mainly, it has shown to promote neuron survival under hypoxia, which could potentially limit brain damage. It is an intracellular hemoprotein expressed in the central and peripheral nervous system, cerebrospinal fluid, retina, and endocrine tissues. It has hexa-coordinated heme-Fe atoms that display O2 affinities comparable to those of myoglobin.

Function
Neuroglobin's exact physiological role is still uncertain. Over time, this protein has evolved extremely slowly compared to the rate of hemoglobin and myoglobin. However, some likely functions are:

1.  Neuroglobin enhances the O2 supply to the mitochondria of the metabolically active neurons. This hypothesis is supported because neuroglobin primarily resides in metabolically active cells and subcellular compartments. Also, the concentration of neuroglobin is closely correlated to the distribution of mitochondria; however, it is not entirely localized in this specific organelle. In neuroglobin, the fast autoxidation of ferrous (Fe2+) neuroglobin to ferric (Fe3+) Neuroglobin observed in vitro would rather inhibit an efficient binding of O2 to neuroglobin, but favors an involvement of neuroglobin in some type of redox reaction (seen below).

2.  In cell culture systems, neuroglobin expression may be induced by hypoxia. It is unlikely that many nervous systems of animals are used to low O2 supply, so this theory is still contradictory. In many species of fish that must rely on lower levels of oxygen, the amount of neuroglobin is much higher than in species that do not deal with this.

3.  Like other types of globin, neuroglobin associates with other gaseous ligands besides O2. Under an excess of NO applied in vitro, an Ngb-Fe2+-NO form is established by reductive nitrosylation, which then decomposes the very toxic ROS component peroxynitrite, resulting in Ngb-Fe3+-NO. Therefore, neuroglobin was proposed to have a similar role to that of Mb, acting as a NO-dioxygenase when PO2 is low and NO levels are increased. Under low-oxygen conditions deoxygenated Ngb may react with NO2–, resulting in the formation of NO.

Conclusion
The recent discovery of neuroglobin, displaying heme hexacoordination has a substantial impact on our understanding of O2 metabolism in man and other vertebrates. The vastly different expression patterns of the four globin types (Hemoglobin, Myoglobin, Neuroglobin and Cytoglobin) strongly suggest diverse roles. Furthermore, it is conceivable that neuroglobin will cast new light on the ancestral function of vertebrate globins in general, and within the nervous system in particular.

Protection against Alzheimer
Scientists have learned that neuroglobin protects cells from stroke damage, amyloid toxicity and injury due to lack of oxygen. Neuroglobin occurs in various regions of the brain and at particularly high levels in brain cells called neurons. Scientists have associated low levels of neuroglobin in brain neurons with increased risk of Alzheimer's disease. Recent studies have hinted that neuroglobin protects cells by maintaining the function of mitochondria and regulating the concentration of important chemicals in the cell. However, the exact mechanisms by which neuroglobin protects cells from dying a natural death has, until now, remained unclear. The study led by UC Davis biomedical engineering professor Subhadip Raychaudhuri and University of Auckland biological sciences Professor Thomas Brittain, found that neuroglobin preserves the functioning of a cell's mitochondria by neutralizing a molecule necessary for the formation of a type of protein that triggers the cell's collapse. The scientists think that the fundamental role of neuroglobin found in neurons is to prevent accidental cell death from occurring due to stress associated with normal cell functioning. Cells may protect themselves from triggering the chain of events leading to cell death by expressing a high level of neuroglobin. Mitochondria are tiny "capsules" within a cell that make most of the raw material the cell uses to produce its energy. Mitochondria also play important roles in communication within and between cells and important aspects of cell differentiation and growth. A cell dies quickly when its mitochondria stop functioning. Various kinds of stressors, such as lack of oxygen, low nutrient levels, increased calcium levels or presence of toxic substances can cause mitochondria to rupture and emit a molecule called cytochrome c. Cytochrome c binds with other molecules outside the mitochondria to form a protein called an apoptosome. The apoptosome helps build an enzyme that degrades and eventually collapses the cell. Neural cells can survive damage to the mitochondria if apoptosomes do not form. For their study, the researchers developed predictions from computational modeling and validated them with biological experiments. They found that neuroglobin binds to cytochrome c and prevents it from forming an apoptosome. This finding could offer new approaches to the prevention and treatment of Alzheimer's disease. In Alzheimer's disease, a toxic type of protein accumulates in brain neurons and leads to mitochondrial rupture and cell death. The finding suggests that high neuroglobin levels may buffer neurons against the effect of this protein by preventing apoptosomes from forming.