Mitochondrial
DNA deletions (mtDNA) have been implicated in the pathogenesis of
Alzheimer's disease (AD), MS and Parkinson's disease (PD), as well as
ageing. Clonal expansion = replication of mtDNA is the process by
which a mutant mtDNA molecule increases to high levels within a single
cell containing both wild-type and mutant mtDNA. Unlike in AD and PD,
the diffuse inflammatory process in MS involves the choroid plexus, and
mitochondria are exposed to reactive oxygen and nitrogen species over a
prolonged period.
The extent of respiratory enzyme deficiency and mtDNA at a single cell level within choroid plexus
epithelial cells in MS as well as in AD, PD and controls. The
respiratory enzyme-deficient
(lacking complex IV and with intact complex II activity) cells were
more prevalent within the choroid plexus in AD, MS and PD compared with
controls. The main catalytic subunit of complex IV (subunit-I of
cytochrome c oxidase) was lacking in significantly more respiratory
enzyme-deficient cells in MS compared with AD, PD and controls. The
single cell analysis showed a fourfold increase in the percentage of
respiratory enzyme-deficient choroid plexus epithelial cells harbouring
clonally expanded mtDNA in MS. Our findings establish clonal expansion
of mtDNA as a feature relatively more prominent within the choroid
plexus epithelium in MS than AD, PD or controls. We propose clonal
expansion of mtDNA as a molecular link between inflammation and part of a
delayed cellular energy failure in MS.