Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom.
Hum Mol Genet. 2023 Dec 12;33(1):91-101. doi: 10.1093/hmg/ddad161.
Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterise the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.
影响线粒体膜间空间蛋白 CHCHD10 的突变可导致人类疾病，但尚不清楚为什么不同的氨基酸取代会导致明显不同的临床表型，包括肌萎缩侧索硬化症-额颞叶痴呆、脊髓性肌萎缩 Jokela 型、孤立性常染色体显性遗传性线粒体肌病和心肌病。CHCHD10 突变与线粒体 DNA（mtDNA）缺失有关，这增加了这些突变解释临床变异性的可能性。在这里，我们对 WT 和 Chchd10 G58R 或 S59L 敲入小鼠的心脏、骨骼肌、肝脏和脊髓中的 mtDNA 进行测序，以表征两种突变系的 mtDNA 缺失特征。我们发现，根据 Chchd10 基因型，G58R 和 S59L 小鼠的某些组织中的缺失水平高于 WT 小鼠，并且缺失负担随年龄增加而增加。此外，我们观察到与其他检查的组织相比，脊髓不太容易发生 mtDNA 缺失。最后，除了加速自然发生的缺失率外，Chchd10 突变还导致一组新的缺失积累，这些缺失的特点是缺失断点侧翼的直接重复较短。我们的结果表明，小鼠中的 Chchd10 突变诱导组织特异性缺失，这也可能导致与这些突变相关的人类临床表型。
