Abstract
Haemoglobins are iron-containing proteins that transport oxygen in the blood of most vertebrates. The mitochondrion is the cellular organelle which consumes oxygen in order to synthesise ATP. Mitochondrial dysfunction is implicated in neurodegeneration and ageing. We find that α and β haemoglobin (Hba and Hbb) proteins are altered in their distribution in mitochondrial fractions from degenerating brain. We demonstrate that both Hba and Hbb are co-localised with the mitochondrion in mammalian brain. The precise localisation of the Hbs is within the inner membrane space and associated with inner mitochondrial membrane. Relative mitochondrial to cytoplasmic ratios of Hba and Hbb show changing distributions of these proteins during the process of neurodegeneration in the pcd5j mouse brain. A significant difference in mitochondrial Hba and Hbb content in the mitochondrial fraction is seen at 31days after birth, this corresponds to a stage when dynamic neuronal loss is measured to be greatest in the Purkinje Cell Degeneration mouse. We also report changes in mitochondrial Hba and Hbb levels in ageing brain and muscle. Significant differences in mitochondrial Hba and Hbb can be seen when comparing aged brain to muscle, suggesting tissue specific functions of these proteins in the mitochondrion. In muscle there are significant differences between Hba levels in old and young mitochondria. To understand whether the changes detected in mitochondrial Hbs are of clinical significance, we examined Parkinson's disease brain, immunohistochemistry studies suggest that cell bodies in the substantia nigra accumulate mitochondrial Hb. However, western blotting of mitochondrial fractions from PD and control brains indicates significantly less Hb in PD brain mitochondria. One explanation could be a specific loss of cells containing mitochondria loaded with Hb proteins. Our study opens the door to an examination of the role of Hb function, within the context of the mitochondrion—in health and disease.
Highlights
Mitochondrial dysfunction is currently under scrutiny for its role in neurodegeneration
Our characterisation of a mitochondrial defect was echoed in the fruit fly ortholog NnaD, and we demonstrate that important neurodegenerative disease pathways can be common across species and are likely to be relevant to a number of human diseases
Neuroglobin, a neuron specific oxygen carrier has been shown to associate in the mitochondrial fraction and to be located within mitochondria we show that haemoglobins are embedded in those regions of the organelle where a continuous supply of oxygen is critical for survival (Lechauve et al, 2012; Yu et al, 2012)
Summary
Mitochondrial dysfunction is currently under scrutiny for its role in neurodegeneration. We have utilised a classic mouse model of neurodegeneration to try and answer questions about the changes that occur early, or pre-symptomatically, in neurons that are destined to undergo a degenerative process. The mouse model Purkinje Cell Degeneration mouse (pcd), shows signs of ataxia soon after weaning (Chakrabarti et al, 2006). Pcd is a natural model of ataxia, resulting from a rapid and complete loss of Purkinje cells in the cerebellum. From about 5 months of age, ataxia is accompanied by other neuronal losses, notably in the photoreceptors of the eye (Chakrabarti et al, 2008). We and others have confirmed that the pcd phenotype is due to the loss of a single protein
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