Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Sci Adv. 2019 Apr 3;5(4):eaav9824. doi: 10.1126/sciadv.aav9824. eCollection 2019 Apr.
Heteroplasmic mtDNA mutations typically act in a recessive way and cause mitochondrial disease only if present above a certain threshold level. We have experimentally investigated to what extent the absolute levels of wild-type (WT) mtDNA influence disease manifestations by manipulating TFAM levels in mice with a heteroplasmic mtDNA mutation in the tRNA gene. Increase of total mtDNA levels ameliorated pathology in multiple tissues, although the levels of heteroplasmy remained the same. A reduction in mtDNA levels worsened the phenotype in postmitotic tissues, such as heart, whereas there was an unexpected beneficial effect in rapidly proliferating tissues, such as colon, because of enhanced clonal expansion and selective elimination of mutated mtDNA. The absolute levels of WT mtDNA are thus an important determinant of the pathological manifestations, suggesting that pharmacological or gene therapy approaches to selectively increase mtDNA copy number provide a potential treatment strategy for human mtDNA mutation disease.
异质体 mtDNA 突变通常以隐性方式起作用，只有在超过一定阈值水平时才会导致线粒体疾病。我们通过在 tRNA 基因中具有异质体 mtDNA 突变的小鼠中操纵 TFAM 水平，实验性地研究了野生型 (WT) mtDNA 的绝对水平在多大程度上影响疾病表现。尽管异质体的水平保持不变，但总 mtDNA 水平的增加改善了多种组织的病理学。mtDNA 水平的降低使有丝分裂后组织（如心脏）的表型恶化，而在快速增殖组织（如结肠）中却出现了意想不到的有益效果，因为这导致了克隆扩展和突变 mtDNA 的选择性消除。因此，WT mtDNA 的绝对水平是病理表现的重要决定因素，这表明选择性增加 mtDNA 拷贝数的药物或基因治疗方法为人类 mtDNA 突变疾病提供了一种潜在的治疗策略。
