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

• Published in: Nature communications Vol. 15; no. 1; pp. 546 - 15
• Main Authors: Yang, Liang, Ruan, Zifeng, Lin, Xiaobing, Wang, Hao, Xin, Yanmin, Tang, Haite, Hu, Zhijuan, Zhou, Yunhao, Wu, Yi, Wang, Junwei, Qin, Dajiang, Lu, Gang, Loomes, Kerry M., Chan, Wai-Yee, Liu, Xingguo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/35; 631/208/737; 631/532; 631/80/642/333; Accumulation; Aging; Homeostasis; Humanities and Social Sciences; In vivo methods and tests; Intestine; Males; Mitochondrial DNA; multidisciplinary; Mutation; NAD; Organoids; Phenotypes; Protein folding; Science; Science (multidisciplinary); Small intestine; Stem cells; Wnt protein; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44808-z

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 (UPR mt ) activation. This aging phenotype is reversed by supplementation with the NAD + precursor, NMN. Thus, we uncover a NAD + dependent UPR mt triggered by mtDNA mutations that regulates the intestinal aging. How age-accumulated mtDNA mutations in the small intestine modulate intestinal homeostasis is unclear. Here, the authors show that increased mtDNA mutation burden triggers an ATF5 dependent UPRmt by NAD + depletion, and thus regulates intestinal aging through impaired Wnt/β-catenin signaling.