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

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...

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Published inNature 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
LanguageEnglish
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
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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 (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.
AbstractList 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.
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.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.
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.
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.
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.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.
ArticleNumber 546
Author Ruan, Zifeng
Wang, Junwei
Yang, Liang
Chan, Wai-Yee
Xin, Yanmin
Zhou, Yunhao
Tang, Haite
Wu, Yi
Liu, Xingguo
Qin, Dajiang
Hu, Zhijuan
Lu, Gang
Loomes, Kerry M.
Lin, Xiaobing
Wang, Hao
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Snippet Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known...
Abstract Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is...
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SubjectTerms 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
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Title NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
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Volume 15
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