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Increased Total mtDNA Copy Number Cures Male Infertility Despite Unaltered mtDNA Mutation Load.
Cell Metabolism ( IF 29.0 ) Pub Date : 2017-Aug-01 , DOI: 10.1016/j.cmet.2017.07.003
Min Jiang , Timo Eino Sakari Kauppila , Elisa Motori , Xinping Li , Ilian Atanassov , Kat Folz-Donahue , Nina Anna Bonekamp , Sara Albarran-Gutierrez , James Bruce Stewart , Nils-Göran Larsson

Mutations of mtDNA cause mitochondrial diseases and are implicated in age-associated diseases and aging. Pathogenic mtDNA mutations are often present in a fraction of all mtDNA copies, and it has been widely debated whether the proportion of mutant genomes or the absolute number of wild-type molecules determines if oxidative phosphorylation (OXPHOS) will be impaired. Here, we have studied the male infertility phenotype of mtDNA mutator mice and demonstrate that decreasing mtDNA copy number worsens mitochondrial aberrations of spermatocytes and spermatids in testes, whereas an increase in mtDNA copy number rescues the fertility phenotype and normalizes testes morphology as well as spermatocyte proteome changes. The restoration of testes function occurs in spite of unaltered total mtDNA mutation load. We thus demonstrate that increased copy number of mtDNA can efficiently ameliorate a severe disease phenotype caused by mtDNA mutations, which has important implications for developing future strategies for treatment of mitochondrial dysfunction.

中文翻译:

尽管mtDNA突变负荷未改变,但增加的mtDNA总拷贝数可治愈男性不育症。

mtDNA突变导致线粒体疾病,并与年龄相关的疾病和衰老有关。致病性mtDNA突变通常出现在所有mtDNA拷贝的一小部分中,并且突变基因组的比例或野生型分子的绝对数量决定了氧化磷酸化(OXPHOS)是否受到损害,这已引起广泛争议。在这里,我们研究了mtDNA变异小鼠的男性不育表型,并证明降低mtDNA拷贝数会使睾丸中精细胞和精子的线粒体畸变恶化,而mtDNA拷贝数的增加可以挽救生育表型,并使睾丸形态和精子细胞形态正常化变化。尽管总mtDNA突变负荷未改变,但睾丸功能仍在恢复。
更新日期:2017-08-24
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