Morphological and functional abnormalities in mitochondria associated with synaptic degeneration in prion disease.
Synaptic and dendritic pathology is a well-documented component of prion disease. In common with other neurodegenerative diseases that contain an element of protein misfolding, little is known about the underlying mechanisms of synaptic degeneration. In particular, in prion disease the relationship between synaptic malfunction, degeneration, and mitochondria has been neglected. We investigated a wide range of mitochondrial parameters, including changes in mitochondrial density, inner membrane ultrastructure, functional properties and nature of mitochondrial DNA from hippocampal tissue of mice with prion disease, which have ongoing synaptic pathology. Our results indicate that despite a lack of detectable changes in either mitochondrial density or expression of the mitochondrial proteins, mitochondrial function was impaired when compared with age-matched control animals. We observed changes in mitochondrial inner membrane morphology and a reduction in the cytochrome c oxidase activity relative to a sustained level of mitochondrial proteins such as porin and individual, functionally important subunits of complex II and complex IV. These data support the idea that mitochondrial dysfunction appears to occur due to inhibition or modification of respiratory complex rather than deletions of mitochondrial DNA. Indeed, these changes were seen in the stratum radiatum where synaptic pathology is readily detected, indicating that mitochondrial function is impaired and could potentially contribute to or even initiate the synaptic pathology in prion disease.
Sisková
Zuzana
Z
CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK. z.siskova@soton.ac.uk
Mahad
Don Joseph
DJ
Pudney
Carianne
C
Campbell
Graham
G
Cadogan
Mark
M
Asuni
Ayodeji
A
O'Connor
Vincent
V
Perry
Victor Hugh
VH
D000818:Animals; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV