Increased mtDNA mutation frequency in oocytes causes epigenetic alterations and embryonic defects

Author:

Han Longsen1,Chen Yujia1,Li Ling12,Ren Chao3,Wang Haichao1,Wu Xinghan1,Ge Juan1,Shu Wenjie3,Chen Minjian14,Wang Qiang15ORCID

Affiliation:

1. State Key Laboratory of Reproductive Medicine, Suzhou Municipal Hospital, Nanjing Medical University , Nanjing 211166 , China

2. Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine , Nanjing 210033 , China

3. Beijing Institute of Microbiology and Epidemiology , Beijing 100850 , China

4. Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University , Nanjing 211166 , China

5. Center for Global Health, School of Public Health, Nanjing Medical University , Nanjing 211166 , China

Abstract

Abstract Mitochondria are essential for female reproductive processes, yet the function of mitochondrial DNA (mtDNA) mutation in oocytes remains elusive. By employing an mtDNA mutator (Polgm) mouse model, we found the fetal growth retardation and placental dysfunction in post-implantation embryos derived from Polgm oocytes. Remarkably, Polgm oocytes displayed the global loss of DNA methylation; following fertilization, zygotic genome experienced insufficient demethylation, along with dysregulation of gene expression. Spindle–chromosome exchange experiment revealed that cytoplasmic factors in Polgm oocytes are responsible for such a deficient epigenetic remodeling. Moreover, metabolomic profiling identified a significant reduction in the α-ketoglutarate (αKG) level in oocytes from Polgm mice. Importantly, αKG supplement restored both DNA methylation state and transcriptional activity in Polgm embryos, consequently preventing the developmental defects. Our findings uncover the important role of oocyte mtDNA mutation in controlling epigenetic reprogramming and gene expression during embryogenesis. αKG deserves further evaluation as a potential drug for treating mitochondrial dysfunction-related fertility decline.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Natural Science Foundation of Jiangsu Province

Publisher

Oxford University Press (OUP)

Subject

Multidisciplinary

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3