The role of mitochondrial dysfunction in Huntington’s disease: Implications for therapeutic targeting

Abstract

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by cognitive decline, motor dysfunction, and psychiatric disturbances. A common feature of neurodegenerative disorders is mitochondrial dysfunction, which affects the brain's sensitivity to oxidative damage and its high oxygen demand. This dysfunction may plays a significant role in the pathogenesis of Huntington’s disease. HD is caused by a CAG repeat expansion in the huntingtin gene, which leads to the production of a toxic mutant huntingtin (mHTT) protein. This disruption in mitochondrial function compromises energy metabolism and increases oxidative stress, resulting in mitochondrial DNA abnormalities, impaired calcium homeostasis, and altered mitochondrial dynamics. These effects ultimately may contribute to neuronal dysfunction and cell death, underscoring the importance of targeting mitochondrial function in developing therapeutic strategies for HD.

This review discusses the mechanistic role of mitochondrial dysfunction in Huntington's disease. Mitochondrial dysfunction is a crucial factor in HD, making mitochondrial-targeted therapies a promising approach for treatment. We explore therapies that address bioenergy deficits, antioxidants that reduce reactive oxygen species, calcium modulators that restore calcium homeostasis, and treatments that enhance mitochondrial dynamics to rejuvenate mitochondrial function. We also highlight innovative treatment approaches such as gene editing and stem cell therapy, which offer hope for more personalized strategies.

In conclusion, understanding mitochondrial dysfunction in Huntington's disease may guide potential treatment strategies. Targeting this dysfunction may help to slow disease progression and enhance the quality of life for individuals affected by Huntington's disease.