Hexokinase I is predominant form of hexokinase family in mammalian brain. But under hypoxic conditions, there is no obvious change in its expression. In contrast, hexokinase II, which is mainly expressed in insulin-sensitive tissues and malignant tumors, experiences a robust upregulation. I think it is a norm that only when a protein's function has been compromised, then its subsitute may undergo a change to adjust to this situation.So my question is why hypoxia exposure can induce a significant uptegulation of hexokinase II whereas it has no effect on hexokinase I in brain? Is it possible that it may play some other roles in hypoxic situations? Thanks ~~
Dear Yuan Lee,
Hexokinase II binds to the mitochondrial membrane through interaction with the outer membrane voltage-dependent anion channel (VDAC), preferentially at contact sites between the outer and inner mitochondrial membrane. This location is important for the integration of glycolysis with mitochondrial energy metabolism, since VDAC interaction with Bcl-2 antiapoptotic proteins controls the rate of release of mitochondrial intermembrane space proteins that activate the execution phase of apoptosis.
Therefore, Hexokinase II binding to VDAC suppresses the mitochondrial permeability transition and inhibits apoptosis, thereby contributing to the neuronal survival of hypoxia. That is why hypoxic conditions upregulate expression of this enzyme.
On the other side, Hexokinase I has no effect on Bcl-2 and apoptosis regulation, which makes it not useful in survival of hypoxic cellular stress.
I hope this helps you.
For more info see:
Chiara, Federica, et al. "Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels." PloS one 3.3 (2008): e1852.
Pastorino, John G., and Jan B. Hoek. "Hexokinase II: the integration of energy metabolism and control of apoptosis." Current medicinal chemistry 10.16 (2003): 1535-1551.
Sorry for the delayed reply. I agree with what you said ,But I may have different opinions,.As for the hypoxia exposure-induced hexokinase II,even some redistributes to mitochondrion to exert a antiapoptotic effect, there still exsits some in cytoplasm or other organelles. Since the basic physilogical function of Hexokinase is to produce G-6-P and the normal function of hexokinase I in brain in a hypoxic condition, there must be a load of lactate accumulation , So how can our brain deal with this situation?
Dear Yuan Li,
If I remenber well, there is what is called "the astrocyte-neuron lactate shuttle" in the brain. The first cell type produce lactate using glycolysis and the second cell type consume this lactate produced in vicinity. I hope this will help you
Thaanks for your suggestion, Olivier Diaz. I have seen this paper before, but the source of lactate is not from neurons themselves. Howeve, under hypoxic conditions, hexokinase II is upregulated in neurons, even they can use lactate as fuel, they may also cause acidification within cells since it is acid.
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