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

作　　者：Longsen Han Yujia Chen Ling Li Chao Ren Haichao Wang Xinghan Wu Juan Ge Wenjie Shu Minjian Chen Qiang Wang 

机构地区：[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

出　　处：《National Science Review》2022年第10期61-75,共15页国家科学评论（英文版）

基　　金：the National Key Research and Development Program of China(2021YFC2700400 to Q.W.);the National Natural Science Foundation of China(81925014 to Q.W.;31900594to L.H.;81872650to M.C.);the Natural Science Foundation of Jiangsu Province(BK20190615 to L.H.).

摘　　要：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.

关 键 词：MTDNA metabolism OOCYTE EMBRYO EPIGENETICS 

分 类 号：R321.1[医药卫生—人体解剖和组织胚胎学]