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HD InsightsMitochondria Dysfunction in Huntington’s Disease

Mitochondrial DNA instability in HD somatic cell types

Mitchondria are a part of the cell critical to cellular energy production and metabolism. There are lines of evidence that suggest that the impact of mutant huntingtin (mtHtt) on this critical cellular organ is associated with HD pathology.

Importantly, mitochondria have their own DNA (mtDNA), which undergoes mutations at a higher rate than nuclear DNA, the DNA that encodes the genome. Dysfunction in nuclear DNA repair has been shown to contribute to HD pathology through somatic instability, leading to further expansion in the HD disease-causing mutation over the course of a cell’s life. Somatic instability is generally observed in cells which are constantly dividing. Now, somatic instability has been found in neurons, which are post-mitotic cells, which means they do not divide over the course of human life.

This led to a question of how mitochondrial quality in HD post-mitotic cells may affect mitochondrial homeostasis. Researchers recently published on their research looking at fresh human skeletal muscle, also a post-mitotic cell type, from HD patients and age-matched controls.1 The paper also examined this in HD cell lines from patients and from HD models. 

Using ultra-deep sequencing on the mtDNA samples, the authors found that maintaining mtDNA homeostasis in these cells was compromised, and this was associated with an increase in pathogenic mtDNA mutations. This suggests that the mitochondria quality is affected over the lifetime of a patient.

They further showed that longer repeats had more severe consequences on the mitochondrial phenotypes, aligning with the understanding that longer repeats cause worse disease as well as somatic instability, leading to the progressive nature of the disease.

Finally, using the cellular model systems, the group showed that the failure in mitochondrial homeostasis control might be in response to, or worsen in, cellular stress situations.

This data suggests that drugs targeting improved mitochondrial quality are a promising path for HD therapeutics.

Impaired transport of mitochondria in HD striatal neurons

Another recent study examined how mitochondrial dysfunction may lead to pathogenesis in HD. The researchers examined how, in striatal neurons, mitochondria may be uniquely affected by expression of mtHtt.2

Mitochondria are transported to neural axons, which have high energy requirements to perform their function of neurotransmission. Mitochondria both travel from the cell body to the axons (anterograde) or from the axons to the cell body (retrograde).

In this study, striatal neurons were isolated from the zQ175 knock-in mouse model of HD, and using a live imaging microscopy technique, the mitochondria and axons were labeled in isolated striatal neurons and the movement of mitochondria was imaged live over time.

The group found dysfunction both in travel distance and speed of mitochondria traveling in the anterograde direction in mtHtt- expressing neurons compared to wildtype control neurons. This suggests that the axons were not receiving the appropriate energy they need to perform their function. The group additionally noted that this dysfunction was specific to mitochondria which are proximal to the cell body, versus those that are distal to the cell body and have travelled further towards the axon.

The group also found that when they overexpressed Mitochondrial Rho GTPase 1
(Miro1) in the mtHtt neurons, they were able to specifically correct the speed and travel length dysfunction of proximal anterograde-moving mitochondria. Miro1 is a protein involved in mitochondrial transport and is known to be decreased in other neurodegenerative diseases like Parkinson’s disease and ALS.

Although there is no difference in the naturally-occurring levels of Miro1 in HD, the authors posit that other dysfunctions in HD may change the ability of Miro1 to correctly perform its function, leading to problematic mitochondrial movement. Therefore, Miro1 and other mitochondrial movement-associated proteins present another promising avenue for HD therapeutic research.

1. Neueder, A. et.al. (2024) Huntington disease affects mitochondrial network dynamics predisposing to pathogenic mtDNA mutations: Brain doi: 10.1093/brain/awae007

2. Chao, W. et.al. (2024) Altered anterograde axonal transport of mitochondria in cultured striatal neurons of a knock-in mouse model of Huntington’s disease: Biochemical and Biophysical Research Communications 691: 149246