Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis.
Mitochondrial DNA deletions (∆-mtDNA) have been implicated in the pathogenesis of Alzheimer's disease (AD), multiple sclerosis (MS) and Parkinson's disease (PD), as well as ageing. Clonal expansion 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. We determined 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.
The Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Graham R
GR
Campbell
Yevgenya
Y
Kraytsberg
Kim J
KJ
Krishnan
Nobuhiko
N
Ohno
Iryna
I
Ziabreva
Amy
A
Reeve
Bruce D
BD
Trapp
Jia
J
Newcombe
Richard
R
Reynolds
Hans
H
Lassmann
Konstantin
K
Khrapko
Doug M
DM
Turnbull
Don J
DJ
Mahad
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002831:Choroid Plexus / Q000378:metabolism* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
D004272:DNA, Mitochondrial