Huntington’s Disease and Mitochondria

Abstract

Huntington's disease (HD) as an inherited neurodegenerative disorder leads to neuronal loss in striatum. Progressive motor dysfunction, cognitive decline, and psychiatric disturbance are the main clinical symptoms of the HD. This disease is caused by expansion of the CAG repeats in exon 1 of the huntingtin which encodes Huntingtin protein (Htt). Various cellular and molecular events play role in the pathology of HD. Mitochondria as important organelles play crucial roles in the most of neurodegenerative disorders like HD. Critical roles of the mitochondria in neurons are ATP generation, Ca buffering, ROS generation, and antioxidant activity. Neurons as high-demand energy cells closely related to function, maintenance, and dynamic of mitochondria. In the most neurological disorders, mitochondrial activities and dynamic are disrupted which associate with high ROS level, low ATP generation, and apoptosis. Accumulation of mutant huntingtin (mHtt) during this disease may evoke mitochondrial dysfunction. Here, we review recent findings to support this hypothesis that mHtt could cause mitochondrial defects. In addition, by focusing normal huntingtin functions in neurons, we purpose mitochondria and Huntingtin association in normal condition. Moreover, mHtt affects various cellular signaling which ends up to mitochondrial biogenesis. So, it could be a potential candidate to decline ATP level in HD. We conclude how mitochondrial biogenesis plays a central role in the neuronal survival and activity and how mHtt affects mitochondrial trafficking, maintenance, integrity, function, dynamics, and hemostasis and makes neurons vulnerable to degeneration in HD.

Mechanisms of protein toxicity in neurodegenerative diseases

“…The mechanisms by which mutant htt proteins induce mitochondrial dysfunction have been shown to be as diverse as that in AD. Aside from the mutant htt perturbing transcription of genes related to mitochondrial biogenesis and function in the nucleus [119, 120], it could also directly interact with mitochondrial proteins [121]. The N-terminal fragment of mutant htt localizes to the mitochondria [122–124] both in vivo and in vitro, and it interacts with the TIM23 complex, thereby clogging the mitochondrial import process [125].…”

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

“…This organelle is mainly responsible for energy production and transfer, crucial for cellular redox and calcium homeostasis, and have a central role in apoptosis (Nicholls and Ferguson, 2013). Disturbed mitochondrial functions have been associated with encephalopathy of common neurological disorders (Farshbaf and Ghaedi, 2017;Guo et al, 2017;Tefera and Borges, 2017;Angelova and Abramov, 2018;Zhou et al, 2018), as well as in brain injury of GA I (Strauss and Morton, 2003;Kölker et al, 2004;Wajner and Goodman, 2011).…”

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

“…Neurodegenerative disease can be caused by exposure to mitochondrial poisons and PD can be caused by mutations in mitochondrial proteins , both of which can lead to mitochondrial respiratory chain dysfunction. In fact, mitochondrial dysfunction of unknown origin is well documented in ALS , PD , HD , and AD . At the time of this writing, a PubMed search for ‘mitochondria’ and ‘neurodegeneration’ reviews exceeded 1500 manuscripts, summarizing the abundance of evidence supporting a key role for mitochondrial pathobiology in neurodegeneration.…”