Journal
AGING CELL
Volume 19, Issue 9, Pages -Publisher
WILEY
DOI: 10.1111/acel.13206
Keywords
aging; fertility; mitochondria; mitochondrial DNA; nicotinamide mononucleotide
Categories
Funding
- National Key Research and Development Program of China [2018YFA0107100, 2017YFA0106300, 2017YFA0102900, 2017YFC1001602, 2019YFA09004500, 2016YFA0100300]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16030505]
- National Natural Science Foundation Projects of China [U1601227, 31631163001, 31701281, 31701106, 31801168, 31900614, 31970709, 81901275]
- Key Research Program of Frontier Sciences, CAS [QYZDB-SSW-SMC001]
- CAS STS Program [KFJ-STS-QYZD-125]
- Guangzhou Health Care and Cooperative Innovation Major Project [201704020218]
- Guangdong Province Science and Technology Program [2017B020230005, 2017A020215056, 2017B030314056, 2018A030313825, 2018GZR110103002, 2020A1515011200, 2020A1515010919, 2020A1515011410]
- Guangzhou Science and Technology Program [201707010178, 201807010067, 202002030277]
- Yangtze River Scholar Bonus Schemes
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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.
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