NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations

Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M. Loomes, Wai-Yee Chan and Xingguo Liu ()
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Liang Yang: Guangzhou Medical University
Zifeng Ruan: Guangzhou Medical University
Xiaobing Lin: Guangzhou Medical University
Hao Wang: Guangzhou Medical University
Yanmin Xin: Guangzhou Medical University
Haite Tang: Guangzhou Medical University
Zhijuan Hu: Guangzhou Medical University
Yunhao Zhou: Guangzhou Medical University
Yi Wu: Guangzhou Medical University
Junwei Wang: Guangzhou Medical University
Dajiang Qin: Chinese Academy of Sciences
Gang Lu: CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong
Kerry M. Loomes: University of Auckland
Wai-Yee Chan: CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong
Xingguo Liu: Guangzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.

Date: 2024
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DOI: 10.1038/s41467-024-44808-z

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