Abstract
Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington’s disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.
Highlights
Mitochondrial dysfunction has been implicated to play a critical role in both aging and as a major contributing factor to the pathogenesis in Huntington’s disease (HD), this disorder is not directly caused by mitochondrial mutations
The disease is caused by the expansion of CAG trinucleotide repeats in the huntingtin (HTT) gene resulting in abnormally long polyglutamine expansions in the huntingtin protein (HTT), which confers toxic functions to the mutant HTT protein
Cells may compensate for the age-related mitochondrial dysfunction by using dynamic compensatory and regulatory mechanisms such as mitochondrial biogenesis and mitophagy, which are mitochondria in the striatal cell body cytoplasm (age F(1,8) = 1.17, p = 0.31; genotype F(1,8) = 4.26, p = 0.073; interaction F(1,8) = 0.01, p = 0.94) and no significant differences between the means of old processes critical for maintaining the functional and structural YAC128 (7.70 ± 0.72%), young YAC128 (8.56 ± 0.98%) and old WT
Summary
Mitochondrial dysfunction has been implicated to play a critical role in both aging and as a major contributing factor to the pathogenesis in Huntington’s disease (HD), this disorder is not directly caused by mitochondrial mutations. Cells may compensate for the age-related mitochondrial dysfunction by using dynamic compensatory and regulatory mechanisms such as mitochondrial biogenesis and mitophagy, which are mitochondria in the striatal cell body cytoplasm (age F(1,8) = 1.17, p = 0.31; genotype F(1,8) = 4.26, p = 0.073; interaction F(1,8) = 0.01, p = 0.94) and no significant differences between the means of old processes critical for maintaining the functional and structural YAC128 (7.70 ± 0.72%), young YAC128 (8.56 ± 0.98%) and old WT integrity of post-mitotic tissues such as the brain and skeletal muscle[34]. To test our hypothesis and to understand the natural changes that occur with aging and in the presence of mHTT, we assessed multiple mitochondrial parameters including morphological changes, mtDNAcn, mtDNA damage, mitochondrial function and transcript levels of genes involved in the mitochondrial dynamics in striatum, cortex and skeletal muscle of YAC128 and wild-type (WT) mice. We found a positive correlation between aging and volume fraction of mitochondria located in axons/dendrite
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