Mitochondrial Dysfunction in Huntington's Disease: Pathogenesis and Therapeutic Opportunities

Huntington's disease (HD) is a prototypical neurodegenerative disease, preferentially disrupting the neurons of the striatum and cortex. Progressive motor dysfunctions, psychiatric dis-turbances, behavioral impairments, and cognitive decline are the clinical symptoms of HD progres-sion. The disease occurs due to expanded CAG repeats in exon 1 of huntingtin protein (mHtt), caus-ing its aggregation. Multiple cellular and molecular pathways are involved in HD pathology. Mito-chondria, as vital organelles have an important role in most neurodegenerative diseases like HD. Over the years, the role of mitochondria in neurons has highly diverged; they not only contribute as a cell power source, but also as dynamic organelles that fragment and then fuse to attain a maximal bioenergetics performance, regulating intracellular calcium homeostasis, reactive oxygen species (ROS) generation, antioxidant activity and involved in apoptotic pathways. Indeed, these events are observed to be affected in HD, resulting in neuronal dysfunction in pre-symptomatic stages. MHtt causes critical transcriptional abnormality by altering the expression of a master co-regulator, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), leading to increased susceptibility to oxidative stress and neuronal degeneration. Moreover, mHtt influences multiple cellular signaling events, which end with mitochondrial biogenesis. Here, we resume recent find-ings that pose mitochondria as an important regulatory organelle in HD and how mHtt affects mito-chondrial function, trafficking and homeostasis and makes neurons prone to degeneration. Besides, we also uncover the mitochondrial-based potential targets and therapeutic approaches with immi-nent or currently ongoing clinical trials.

Automated summary

Huntington's disease is a neurodegenerative disorder that primarily affects the neurons of the striatum and cortex, leading to progressive symptoms such as motor dysfunction and psychiatric disturbances. The disease is caused by abnormal protein aggregation, affecting multiple cellular and molecular pathways, particularly with a significant role of mitochondria. Research suggests that the abnormalities caused by the huntingtin protein can impact mitochondrial function, trafficking, and homeostasis, making neurons more susceptible to degeneration.