Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases are incurable and devastating neurological disorders characterized by the progressive loss of the structure and function of neurons in the central nervous system or peripheral nervous system. Mitochondria, organelles found in most eukaryotic cells, are essential for neuronal survival and are involved in a number of neuronal functions. Mitochondrial dysfunction has long been demonstrated as a common prominent early pathological feature of a variety of common neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Mitochondria are highly dynamic organelles that undergo continuous fusion, fission, and transport, the processes of which not only control mitochondrial morphology and number but also regulate mitochondrial function and location. The importance of mitochondrial dynamics in the pathogenesis of neurodegenerative diseases has been increasingly unraveled after the identification of several key fusion and fission regulators such as Drp1, OPA1, and mitofusins. In this review, after a brief discussion of molecular mechanisms regulating mitochondrial fusion, fission, distribution, and trafficking, as well as the important role of mitochondrial dynamics for neuronal function, we review previous and the most recent studies about mitochondrial dynamic abnormalities observed in various major neurodegenerative diseases and discuss the possibility of targeting mitochondrial dynamics as a likely novel therapeutic strategy for neurodegenerative diseases.

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

“…Mutations in the SOD1 gene is the most reported cause for ALS pathogenesis and respiratory failure and pneumonia are the most common causes of death in ALS patients from 3 to 5 years after diagnosis. Currently, the only drugs approved by the FDA for treating ALS are Riluzole and Edaravone, which are the glutamate release inhibitor and free radical scavenger, so the development and application of new drugs (Table ) is imminent (Altanbyek et al, ; Chaturvedi & Flint Beal, ; Gao et al, ; Joshi, Saw, Vogel et al, ; Liu et al, ).…”

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…Similarly, tau, especially hyperphosphorylated tau, disrupts mitochondrial transport in neuronal cells. An Aβ-or APP-induced mitochondrial trafficking deficit could be alleviated by inhibiting mitochondrial fragmentation, indicating the impairment of mitochondrial movement possibly downstream of mitochondrial fragmentation [40].…”

“…Excessive mitochondrial fission (fragmentation) is a prominent early event, contributing to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of AD [40,71,72]. Moreover, mitochondria fragmentation, like a mitochondrial bioenergetic deficit, is an early feature preceding AD pathology in APP transgenic animal models [40] and mouse model CRND8 [73].…”

“…Moreover, mitochondria fragmentation, like a mitochondrial bioenergetic deficit, is an early feature preceding AD pathology in APP transgenic animal models [40] and mouse model CRND8 [73].…”

“…Evidence is presented suggesting amyloid oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, additional cofactors are required [13]. Those cofactors include several subcellular processes including oxidative damage [10,[14][15][16][17][18][19][20][21][22][23], recruitment of peripheral immune cells and excessive production of pro-inflammatory mediators [10,[24][25][26][27][28][29], mitochondrial impairments and chronic energy imbalance [12,20,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], chronic endoplasmic reticulum (ER) stress [48] and autophagy dysfunction [22,[49][50][51][52][53][54], the abnormality and dysfunction of MAM (the mitocho...…”