Title:Mitochondrial Dysfunction in Huntington’s Disease: Pathogenesis and Therapeutic Opportunities
Volume: 22
Issue: 14
Author(s): Aditi Sharma, Tapan Behl*, Lalit Sharma, Lotfi Aelya and Simona Bungau
Affiliation:
- Chitkara College of Pharmacy, Chitkara University, Punjab,India
Keywords:
Huntington disease, mitochondria, oxidative stress, chaperones, ROS, CAG.
Abstract: Huntington’s disease (HD) is a prototypical neurodegenerative disease, preferentially
disrupting the neurons of the striatum and cortex. Progressive motor dysfunctions, psychiatric disturbances,
behavioral impairments, and cognitive decline are the clinical symptoms of HD progression.
The disease occurs due to expanded CAG repeats in exon 1 of huntingtin protein (mHtt), causing
its aggregation. Multiple cellular and molecular pathways are involved in HD pathology. Mitochondria,
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-1α (PGC-1α), 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 findings
that pose mitochondria as an important regulatory organelle in HD and how mHtt affects mitochondrial
function, trafficking and homeostasis and makes neurons prone to degeneration. Besides,
we also uncover the mitochondrial-based potential targets and therapeutic approaches with imminent
or currently ongoing clinical trials.
