Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox. Issue 9 (3rd August 2020)

• Record Type: Journal Article
• Authors: Yang, Liang; Lin, Xiaobing; Tang, Haite; Fan, Yuting; Zeng, Sheng; Jia, Lei; Li, Yukun; Shi, Yanan; He, Shujing; Wang, Hao; Hu, Zhijuan; Gong, Xiao; Liang, Xiaoyan; Yang, Yi; Liu, Xingguo
• Is Part Of: Aging cell. Volume 19:Issue 9(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-08-03
• Subjects: aging -- fertility -- mitochondria -- mitochondrial DNA -- nicotinamide mononucleotide; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13206
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: 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. Abstract : Oocyte accumulates more mtDNA point mutations than sperm during aging, thus exacerbating female's fertility through reducing its NADH/NAD+ redox ratio, which could be rescued by NMN.