2. Academic Validation
  3. Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA

Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA

  • Nat Aging. 2024 Jul 29. doi: 10.1038/s43587-024-00672-6.
Yanfei Ru # 1 2,  Xiaoling Deng # 1 2 3,  Jiatong Chen # 1 2 4,  Leping Zhang # 1 2 4,  Zhe Xu 1 2,  Qunyu Lv 1 2 4,  Shiyun Long 1 2 4,  Zijian Huang 1 2 3,  Minghua Kong 1 2 5,  Jing Guo 6 7,  Min Jiang 8 9 10
Affiliations

Affiliations

  • 1 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
  • 2 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences,Westlake University, Hangzhou, China.
  • 3 Fudan University, Shanghai, China.
  • 4 College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 5 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.
  • 6 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
  • 7 NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, China.
  • 8 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. jiangmin@westlake.edu.cn.
  • 9 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences,Westlake University, Hangzhou, China. jiangmin@westlake.edu.cn.
  • 10 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. jiangmin@westlake.edu.cn.
  • # Contributed equally.
PMID: 39075271 DOI: 10.1038/s43587-024-00672-6
Abstract

Mitochondrial diseases, caused mainly by pathogenic mitochondrial DNA (mtDNA) mutations, pose major challenges due to the lack of effective treatments. Investigating the patterns of maternal transmission of mitochondrial diseases could pave the way for preventive approaches. In this study, we used DddA-derived cytosine base editors (DdCBEs) to generate two mouse models, each haboring a single pathogenic mutation in complex I genes (ND1 and ND5), replicating those found in human patients. Our findings revealed that both mutations are under strong purifying selection during maternal transmission and occur predominantly during postnatal oocyte maturation, with increased protein synthesis playing a vital role. Interestingly, we discovered that maternal age intensifies the purifying selection, suggesting that older maternal age may offer a protective effect against the transmission of deleterious mtDNA mutations, contradicting the conventional notion that maternal age correlates with increased transmitted mtDNA mutations. As collecting comprehensive clinical data is needed to understand the relationship between maternal age and transmission patterns in humans, our findings may have profound implications for reproductive counseling of mitochondrial diseases, especially those involving complex I gene mutations.

Figures
Products