Huntington's disease (HD) primarily affects the brain, causing movement disorders, cognitive decline, and behavioral abnormalities. It also impacts peripheral tissues, including skeletal muscle, where mitochondrial dysfunction has been observed. Mutant huntingtin protein (mutHTT) expression can impair mitochondrial quality control and accelerate mitochondrial aging. In this study, researchers examined fresh human skeletal muscle and primary cell lines from HD patients and healthy volunteers to investigate mitochondrial dynamics in HD. Using ultra-deep mitochondrial DNA (mtDNA) sequencing, they found an accumulation of mtDNA mutations affecting oxidative phosphorylation. Proteomic analysis revealed impairments in mtDNA maintenance and increased mitochondrial biogenesis of less efficient oxidative phosphorylation. In primary cell lines expressing full-length mutHTT, mitochondrial stress resulted in normal mitophagy. However, high levels of N-terminal mutHTT fragments promoted mitochondrial fission and slower, less dynamic mitophagy. The study concludes that lifelong expression of mutant HTT causes a mitochondrial phenotype indicative of mtDNA instability in fresh post-mitotic human skeletal muscle. This suggests that genomic instability may extend beyond nuclear DNA, where it leads to somatic expansion of the HTT CAG repeat length in vulnerable cells like striatal neurons. Promoting mitochondrial health may be a complementary strategy to target the causative mutation in treating diseases with DNA instability, such as HD.Huntington's disease (HD) primarily affects the brain, causing movement disorders, cognitive decline, and behavioral abnormalities. It also impacts peripheral tissues, including skeletal muscle, where mitochondrial dysfunction has been observed. Mutant huntingtin protein (mutHTT) expression can impair mitochondrial quality control and accelerate mitochondrial aging. In this study, researchers examined fresh human skeletal muscle and primary cell lines from HD patients and healthy volunteers to investigate mitochondrial dynamics in HD. Using ultra-deep mitochondrial DNA (mtDNA) sequencing, they found an accumulation of mtDNA mutations affecting oxidative phosphorylation. Proteomic analysis revealed impairments in mtDNA maintenance and increased mitochondrial biogenesis of less efficient oxidative phosphorylation. In primary cell lines expressing full-length mutHTT, mitochondrial stress resulted in normal mitophagy. However, high levels of N-terminal mutHTT fragments promoted mitochondrial fission and slower, less dynamic mitophagy. The study concludes that lifelong expression of mutant HTT causes a mitochondrial phenotype indicative of mtDNA instability in fresh post-mitotic human skeletal muscle. This suggests that genomic instability may extend beyond nuclear DNA, where it leads to somatic expansion of the HTT CAG repeat length in vulnerable cells like striatal neurons. Promoting mitochondrial health may be a complementary strategy to target the causative mutation in treating diseases with DNA instability, such as HD.