Modulation of Mitochondrial Dynamics in Neurodegenerative Diseases: An Insight Into Prion Diseases

Gao

Sig Transduct Target Ther

et al. 2021

193

152

As the crucial powerhouse for cell metabolism and tissue survival, the mitochondrion frequently undergoes morphological or positional changes when responding to various stresses and energy demands. In addition to intracellular changes, mitochondria can also be transferred intercellularly. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, the intercellular mitochondrial transfer also occurs under physiological conditions. In this review, the phenomenon of mitochondrial transfer is described according to its function under both physiological and pathological conditions, including tissue homeostasis, damaged tissue repair, tumor progression, and immunoregulation. Then, the mechanisms that contribute to this process are summarized, such as the trigger factors and transfer routes. Furthermore, various perspectives are explored to better understand the mysteries of cell–cell mitochondrial trafficking. In addition, potential therapeutic strategies for mitochondria-targeted application to rescue tissue damage and degeneration, as well as the inhibition of tumor progression, are discussed.

Section: Perspectives and Applicationsmentioning

confidence: 99%

Intercellular mitochondrial transfer as a means of tissue revitalization

Gao

Sig Transduct Target Ther

et al. 2021

193

152

“…Neurons are cells of extremely high energy demand and are thus particularly vulnerable to mitochondrial dysfunction. Alterations in the mitochondrial network and consequent mitochondrial dysfunction have been suggested to occur as prominent early features in neurodegenerative diseases [ 90 ]. Nowadays, there is an increasing number of neurodegenerative disorders that are associated with mutations in mitochondrial fusion genes.…”

Section: Mitochondrial Dynamics and Associated Diseasesmentioning

confidence: 99%

When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

Kyriakoudi

Drousiotou

Petrou

2021

IJMS

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

Front. Bioeng. Biotechnol.

“…However, studies analyzing other molecular pathways related to autophagy report an increase of autophagy activity at late stages of the disease. For example, mitochondrial dysfunction is a common and prominent feature of prion diseases ( Zhu et al, 2018 ). Mitophagy, which is the specific autophagic elimination of defective mitochondria, is activated in prion-infected SMB-S15 cells and in mice infected with scrapie strains 139A and ME7 at the terminal stage of the disease, represented by the transcriptional and protein increase of the two essential elements regulating mitophagy activity: PINK1 (PTEN-induced kinase 1) and Parkin ( Gao et al, 2020 ).…”

Section: Autophagy In Prion Diseasesmentioning

confidence: 99%

An Update on Autophagy in Prion Diseases

López-Pérez

Badiola

Bolea

et al. 2020

Autophagy is a dynamic intracellular mechanism involved in protein and organelle turnover through lysosomal degradation. When properly regulated, autophagy supports normal cellular and developmental processes, whereas defects in autophagic degradation have been associated with several pathologies, including prion diseases. Prion diseases, or transmissible spongiform encephalopathies (TSE), are a group of fatal neurodegenerative disorders characterized by the accumulation of the pathological misfolded isoform (PrP Sc ) of the physiological cellular prion protein (PrP c ) in the central nervous system. Autophagic vacuoles have been described in experimental models of TSE and in the natural disease in humans. The precise connection of this process with prion-related neuropathology, or even whether autophagy is completely beneficial or pathogenic during neurodegeneration, is poorly understood. Thus, the biological role of autophagy in these diseases is still open to debate. During the last years, researchers have used a wide range of morphological, genetic and biochemical methods to monitor and manipulate the autophagic pathway and thus determine the specific role of this process in TSE. It has been suggested that PrP c could play a crucial role in modulating the autophagic pathway in neuronal cells, and the presence of abnormal autophagic activity has been frequently observed in several models of TSE both in vitro and in vivo , as well as in human prion diseases. Altogether, these findings suggest that autophagy is implicated in prion neuropathology and points to an impairment or failure of the process, potentially contributing to the pathogenesis of the disease. Additionally, autophagy is now emerging as a host defense response in controlling prion infection that plays a protective role by facilitating the clearance of aggregation-prone proteins accumulated within neurons. Since autophagy is one of the pathways of PrP Sc degradation, and drug-induced stimulation of autophagic flux (the dynamic process of autophagic degradation activity) produces anti-prion effects, new treatments based on its activation have been tested to develop therapeutic strategies for prion diseases. In this review, we summarize previous and recent findings concerning the role of autophagy in TSE.