Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox.,Aging Cell

当前位置： X-MOL 学术 › Aging Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox.
Aging Cell ( IF 8.0 ) Pub Date : 2020-08-03 , DOI: 10.1111/acel.13206
Liang Yang _{1,

2} , Xiaobing Lin _{1,

2} , Haite Tang _{1,

2} , Yuting Fan ₃ , Sheng Zeng ₄ , Lei Jia ₃ , Yukun Li _{1,

2} , Yanan Shi ₃ , Shujing He ₃ , Hao Wang _{1,

2} , Zhijuan Hu _{1,

2} , Xiao Gong ₅ , Xiaoyan Liang ₃ , Yi Yang ₆ , Xingguo Liu _{1,

2}

Affiliation

CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China.
The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China.
Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai, China.

Mammals' aging is correlated with the accumulation of somatic heteroplasmic mitochondrial DNA (mtDNA) mutations. Whether and how aging accumulated mtDNA mutations modulate fertility remains unknown. Here, we analyzed oocyte quality of young (≤30 years old) and elder (≥38 years old) female patients and show the elder group had lower blastocyst formation rate and more mtDNA point mutations in oocytes. To test the causal role of mtDNA point mutations on infertility, we used polymerase gamma (POLG) mutator mice. We show that mtDNA mutation levels inversely correlate with fertility, interestingly mainly affecting not male but female fertility. mtDNA mutations decrease female mice's fertility by reducing ovarian primordial and mature follicles. Mechanistically, accumulation of mtDNA mutations decreases fertility by impairing oocyte's NADH/NAD⁺ redox state, which could be rescued by nicotinamide mononucleotide treatment. For the first time, we answer the fundamental question of the causal effect of age‐accumulated mtDNA mutations on fertility and its sex dependence, and show its distinct metabolic controlling mechanism.

中文翻译：

线粒体 DNA 突变通过 NADH/NAD+ 氧化还原损伤加剧女性生殖衰老。

哺乳动物的衰老与体细胞异质线粒体 DNA (mtDNA) 突变的积累有关。衰老积累的 mtDNA 突变是否以及如何调节生育能力仍然未知。在这里，我们分析了年轻（≤30 岁）和老年（≥38 岁）女性患者的卵母细胞质量，结果表明老年组的卵母细胞囊胚形成率较低，mtDNA 点突变较多。为了测试 mtDNA 点突变对不孕症的因果作用，我们使用了聚合酶 γ (POLG) 增变小鼠。我们表明，mtDNA 突变水平与生育能力呈负相关，有趣的是，主要影响的不是男性而是女性生育能力。mtDNA 突变通过减少卵巢原始和成熟卵泡来降低雌性小鼠的生育能力。从机制上讲，mtDNA 突变的积累通过损害卵母细胞的 NADH/NAD 来降低生育能力⁺氧化还原状态，可以通过烟酰胺单核苷酸处理来挽救。我们首次回答了年龄累积的 mtDNA 突变对生育能力及其性别依赖性的因果影响这一基本问题，并展示了其独特的代谢控制机制。

更新日期：2020-09-24

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11