Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission

Abstract

Huntington’s disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.

Cdk5-mediated mitochondrial fission: A key player in dopaminergic toxicity in Huntington's disease

“…Though the precise molecular mechanisms leading to this specific cell death are unknown, growing evidence have emerged for impaired mitochondrial function as a causative factor [34,35]. In this view, here, we have reported in a precise genetic HD striatal cell line and in HD striatal cell cultures impaired mitochondrial dynamics manifested as higher mitochondrial fragmentation and decreased mitochondrial branching compared to wild-type striatal cells, which is consistent with previous studies reporting, in different HD models, altered levels of fission/fusion proteins and increased mitochondrial fission [17,24,36].…”

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…In neurodegenerative diseases, such as AD, high levels of ROS and defective mitochondrial function have been observed (Reddy, 2014). This is in congruence with the "free radical theory" of aging (Harman, 1956) which suggests that aging and neurodegenerative diseases, could be attributed to the toxic effects free radicals have on various cell constituents.…”

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

“…D7‐Des expression also caused a reduction in mitochondrial respiration in both isolated mitochondria and intact cardiomyocytes. Neurodegenerative protein aggregation diseases such as Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and Parkinson disease also exhibit excessive mitochondrial fission, producing increased levels of reactive oxygen species and defective mitochondrial function 48, 49, 50. Biochemical studies of the causative mutant proteins including amyloid β, phosphorylated Tau, mutant Htt, mutant LRRK2, or mutant DJ1 document interactions with mitochondria in affected neurons.…”