Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington’s disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

在诊断为亨廷顿病 (HD) 的患者的大脑和外周组织中发现线粒体功能障碍，这是一种不可逆的神经退行性疾病，衰老是其主要危险因素。线粒体功能不仅由核 DNA 编码，还由线粒体内的 DNA (mtDNA) 编码。mtDNA 异质性的扩展（突变型和野生型 mtDNA 的共存）可导致与年龄相关的线粒体功能下降，但尚未在 HD 中进行系统研究。在这里，通过使用敏感的 mtDNA 靶向测序方法，我们研究了 HD 患者淋巴母细胞和纵向血液样本中的 mtDNA 异质性。我们发现，与来自 182 名健康个体的淋巴母细胞相比，来自 1,549 名 HD 患者的淋巴母细胞中具有预测致病性的 mtDNA 异质性的比例显着增加。HD 淋巴母细胞中致病性 mtDNA 异质性的比例增加也与 HD 阶段的进展和通过 HD 运动功能、认知功能和功能能力衡量的疾病严重程度恶化相关。值得注意的是，拉长的 CAG 在HTT促进了 HD 淋巴母细胞中致病性 mtDNA 异质性的年龄依赖性扩张。我们随后在 169 名 HD 患者的纵向血液样本中证实，在 6 年的中位随访期间，致病性 mtDNA 异质性的扩大与功能能力的下降以及 HD 运动和认知功能的恶化相关。我们的研究结果表明 HD 中 mtDNA 质量加速下降，并强调纵向监测 mtDNA 异质性，作为研究衰老和年龄相关疾病中线粒体功能进行性下降的一种方式。