Desai, R; (2015) A study of mitochondrial biogenesis in the rodent nervous system. Doctoral thesis , UCL (University College London).

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Abstract

This thesis investigates the process of mitochondrial biogenesis in the rodent CNS in the context of neuroinflammatory and neurodegenerative disease. There is mounting evidence of mitochondrial damage in neuroinflammation but very little is known about the turnover of mitochondria in neurones. We developed a method to assess mitochondrial biogenesis by tagging replicating mitochondrial DNA with bromodeoxyurine (BrdU), and used the method to examine mitochondrial biogenesis. In healthy motor neurons, mitochondria were distributed throughout the cell, including the axons, but the DNA replication signal initially only appeared in the cell body, subsequently becoming distributed away from the soma suggesting the presence of a mitochondrial ‘nursery’ in the cell body of long neurones. Furthermore, neuronal DNA replication increased in response to raised energy demand resulting from unilateral electrical stimulation of the sciatic nerve, indicating that mitochondrial biogenesis is promptly responsive to energy demand. Mitochondrial biogenesis was also examined in spinal cord neurons in a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), and the degree of mtDNA replication was compared with the amount of inflammation in the tissue. We found that in severely inflamed tissue mitochondrial biogenesis was significantly reduced in the motor neurones. However, under subtle inflammation in EAE as well as with local intraspinal injection of LPS (lipopolysaccharide), there was an increase in mitochondrial biogenesis, which may be a compensatory mechanism. In separate experiments the CNS was examined globally using the BrdU method, which revealed the presence of hotspots of neuronal mtDNA replication indicating marked differences in mitochondrial turnover. Interestingly, these hotspots represented regions known to undergo degeneration in neurological diseases, especially those known or suspected to have a mitochondrial component in their aetiology. The current findings reveal that mitochondrial biogenesis is substantial in neurons with long axons, and that it is promptly responsive to changing energy and disease conditions.

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