Impairment of Neuronal Mitochondrial Quality Control in Prion-Induced Neurodegeneration

Abstract

Mitochondrial dynamics continually maintain cell survival and bioenergetics through mitochondrial quality control processes (fission, fusion, and mitophagy). Aberrant mitochondrial quality control has been implicated in the pathogenic mechanism of various human diseases, including cancer, cardiac dysfunction, and neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and prion disease. However, the mitochondrial dysfunction-mediated neuropathological mechanisms in prion disease are still uncertain. Here, we used both in vitro and in vivo scrapie-infected models to investigate the involvement of mitochondrial quality control in prion pathogenesis. We found that scrapie infection led to the induction of mitochondrial reactive oxygen species (mtROS) and the loss of mitochondrial membrane potential (ΔΨm), resulting in enhanced phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and its subsequent translocation to the mitochondria, which was followed by excessive mitophagy. We also confirmed decreased expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes and reduced ATP production by scrapie infection. In addition, scrapie-infection-induced aberrant mitochondrial fission and mitophagy led to increased apoptotic signaling, as evidenced by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. These results suggest that scrapie infection induced mitochondrial dysfunction via impaired mitochondrial quality control processes followed by neuronal cell death, which may have an important role in the neuropathogenesis of prion diseases.

Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior

“…Specifically, aberrant mitochondrial quality control (i.e., dysfunctional mitophagy) has been implicated as contributing to the pathogenesis of numerous human diseases, including cancer, cardiac dysfunction, and neurological disorders, notably prion disease (Kim et al 2022 ). For example, Kim and colleagues (Kim et al 2022 ). used scrapie-infected experimental models to explore the role of mitochondrial quality control in disease pathogenesis.…”

Aberrant SENP1-SUMO-Sirt3 Signaling Causes the Disturbances of Mitochondrial Deacetylation and Oxidative Phosphorylation in Prion-Infected Animal and Cell Models

“…On the other hand, such reversion cannot happen in prion-infected brains in vivo with high probability, unless the deposited PrP Sc can be completely removed. Based on the data in our study, one may assume that the abnormality of SENP-SUMO-Sirt3 signaling and mitochondrial acetylation is likely to lead to the mitochondrial disturbance that is one of the common features of prion infection, ,, in which SUMOylation might contribute to neuropathology. However, the consequences of SUMOylation in neurodegeneration are much more complicated and somehow contradictory, such as in the contexts of accelerating or reducing the aggregations of disease-associated misfolded proteins and the neuroprotective or neurotoxic effectiveness .…”

A mouse xenograft long‐term replication yields a SARS‐CoV‐2 Delta mutant with increased lethality

“…Primary embryonic neurons were prepared from 16‐day‐old embryos of pregnant K18‐hACE2 transgenic mice and cultured as previously described 33 . Briefly, embryonic brains were dissected, the skulls were removed, and the brain tissues were minced with surgical blades.…”