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

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

doi:10.1093/nsr/nwac136

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

Natl Sci Rev. 2022 Jul 13;9(10):nwac136. doi: 10.1093/nsr/nwac136. eCollection 2022 Oct.

Authors

Longsen Han¹, Yujia Chen¹, Ling Li^{1

2}, Chao Ren³, Haichao Wang¹, Xinghan Wu¹, Juan Ge¹, Wenjie Shu³, Minjian Chen^{1

4}, Qiang Wang^{1

5}

Affiliations

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

Mitochondria are essential for female reproductive processes, yet the function of mitochondrial DNA (mtDNA) mutation in oocytes remains elusive. By employing an mtDNA mutator (Polg^m) mouse model, we found the fetal growth retardation and placental dysfunction in post-implantation embryos derived from Polg^m oocytes. Remarkably, Polg^m 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 Polg^m 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 Polg^m mice. Importantly, αKG supplement restored both DNA methylation state and transcriptional activity in Polg^m 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.

Keywords: embryo; epigenetics; metabolism; mtDNA; oocyte.