Researchers Discover the Regulatory Mechanism of mtDNA Mutations on Small Intestine Aging

The intestine is the main digestive organ and the largest immune detoxification organ of the human body. Its dysfunction will seriously affect people's physical and mental health through metabolism, nerves, endocrine and immunity. Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, whether and how age-accumulated mtDNA mutations regulate intestinal aging are still unclear.

The research of LIU Xingguo's team at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, was published in the Nature Communications titled “NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations”. It reveals that the accumulation of mtDNA mutations results in NAD+ depletion, and exacerbates intestinal aging by activating the activating transcription factor 5 (ATF5) dependent mitochondrial unfolded protein response (UPRmt). The aging phenotypes could be reversed by supplementing NAD+ precursor, nicotinamide mononucleotide (NMN).

Researchers found an accumulation of mtDNA mutations in mouse intestines during physiological aging process, indicating a correlation between mtDNA mutations and intestinal aging. With a mouse model of premature aging caused by mtDNA mutations, researchers noticed a negative relationship between the level of mtDNA mutations and the aging phenotypes of the small intestine.

By organoid technology and in vivo intestinal stem cell labeling, further investigation showed that increased mtDNA mutation burden resulted in NAD+ depletion during intestinal aging with subsequent activation of the ATF5 dependent UPRmt, and regulated mtDNA mutation-induced aging phenotypes and LGR5 positive ISC exhaustion through impaired Wnt/β-catenin signaling.

This research develops a reverse aging strategy by supplementing NAD+ precursor NMN (nicotinamide mononucleotide), which for the first time answers the basic question of the causal relationship between accumulated mtDNA mutations and mammalian intestinal aging, and provides the molecular mechanism by which mtDNA mutations regulate intestinal aging through mitochondrial reverse signaling.

Overall, this research demonstrates that the accumulation of mtDNA mutations will trigger small intestinal aging in mice, directly explaining the causal relationship between mtDNA mutations and aging. Mechanistically, it also proves the mitochondria-nucleus communication pathway through ATF5-dependent UPRmt and the rescue effect of NAD+ supplement NMN, providing a new theory for studying mitochondrial aging biology.

This research was completed by several research groups, including Guangzhou Medical University, Hong Kong Institute of Science & Innovation of Chinese Academy of Sciences, the Chinese University of Hong Kong and the University of Auckland. This study has received funding support from national key research and development projects, the Chinese Academy of Sciences, the National Natural Science Foundation of China, Guangdong Province, and Guangzhou Municipality.

The regulatory mechanism of mtDNA mutations on small intestinal aging(Image by GIBH)

Contacts:

LIU Xingguo,Ph.D, Principal Investigator;

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

Guangzhou, China, 510530

Email:liu_xingguo@gibh.ac.cn