Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

Abstract

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. Mitochondria are vital organelles in all eukaryotic cells and are responsible for the efficient generation of highenergy compounds such as ATP produced by oxidativephosphorylation system, also called the respiratory chain. The mitochondrial respiratory chain is located in the inner mitochondrial membrane and consists of five complexes (complexes I-V), each consisting of multiple subunits encoded by both nuclear and mitochondrial DNA (mtDNA), except complex II or succinate dehydrogenase (SDH) that is entirely encoded by nuclear DNA.

Cytosolic caspases mediate mislocalised SOD2 depletion in an in vitro model of chronic prion infection

“…Because levels of the mitochondrially localised SOD2 were decreased in chronically infected cells, mitochondrial representation within the cell was considered, but no difference was seen between the overall mock and infected populations. This lack of change is consistent with the investigations of Sisková et al, who found no prion-disease-associated changes in mitochondrial density or expression of mitochondrial proteins (Sisková et al, 2010). The same study did find changes to the mitochondrial inner membrane morphology and reduced cytochrome c oxidase activity, and similar observations were also made by others (Choi et al, 1998; Lee et al, 1999).…”

The ultrastructural characteristics of porcine hepatocytes donated after cardiac death and preserved with warm machine perfusion preservation

“…At high magnification, although the intravacuolar mitochondria were slightly swollen (Fig 5B, colored purple), cytoplasmic mitochondria rather maintained a functional small morphology and the cristae (Fig 5B, colored green). Mitochondrial swelling, generally reflected by an increase of the mitochondrial area is a well-accepted hallmark of dysfunction of this organelle [51,52]. Mitochondria area measurements in hepatocytes showed that the MMP significantly suppressed the increasing of mitochondria area compared to HMP (Fig 5C, HMP_4h vs. MMP_4h, 0.68±0.02 vs. 0.39±0.02 μm 2 per mitochondria, *P<0.0001).…”

Analyses of the mitochondrial mutations in the Chinese patients with sporadic Creutzfeldt–Jakob disease

“…In prion diseases, the impairment of mitochondrial function is repeatedly observed, which could potentially contribute to or even initiate the various abnormalities, for example, synaptic pathology, 24 faulty calcium metabolism, 25 high level of ROS, 26 and apoptosis of neurons. 27 However, it has still been unclear whether mtDNA mutations as a risk factor for sCJD.…”