Bečanović Kristina, Asghar Muhammad, Gadawska Izabella, Sachdeva Shiny, Walker David, Lazarowski Eduardo R, Franciosi Sonia, Park Kevin H J, Côté Hélène C F, Leavitt Blair R
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
NPJ Aging Mech Dis. 2021 Oct 14;7(1):26. doi: 10.1038/s41514-021-00079-2.
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.
线粒体功能障碍和生物能量学衰竭是亨廷顿舞蹈病（HD）和衰老过程中常见的病理特征。在本研究中，我们使用HD的YAC128小鼠模型来研究突变型亨廷顿蛋白对大脑和骨骼肌中与衰老相关的线粒体参数的影响。我们对YAC128小鼠的线粒体DNA变化进行了一项横断面自然史研究。在此，我们首先表明，老年小鼠纹状体神经元细胞体附近的轴突和树突区域中线粒体体积分数似乎增加。线粒体DNA拷贝数（mtDNAcn）被用作线粒体生物发生和功能的替代指标。我们观察到，mtDNAcn随年龄和基因型以组织特异性方式发生显著变化。我们发现衰老与纹状体和骨骼肌中的mtDNAcn呈正相关，但在皮质中并非如此。值得注意的是，YAC128小鼠皮质和骨骼肌中的mtDNAcn较低。我们进一步表明，年轻和老年的YAC128和野生型小鼠的纹状体和骨骼肌组织中均存在mtDNA缺失。通过对小鼠进行横断面追踪基因表达水平，我们能够确定年龄和基因型对线粒体相关基因转录变异的影响。这些发现为线粒体动力学在大脑和骨骼肌HD发病机制中的作用提供了见解，并表明骨骼肌组织中的mtDNAcn可能是一种潜在的生物标志物，应在人类HD中进一步研究。
