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NAD⁺ dependent UPR^mt activation underlies intestinal aging caused by mitochondrial DNA mutations.

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.

SUBMITTER: Yang L

PROVIDER: S-EPMC10791663 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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NAD<sup>+</sup> dependent UPR<sup>mt</sup> activation underlies intestinal aging caused by mitochondrial DNA mutations.

Yang Liang L Ruan Zifeng Z Lin Xiaobing X Wang Hao H Xin Yanmin Y Tang Haite H Hu Zhijuan Z Zhou Yunhao Y Wu Yi Y Wang Junwei J Qin Dajiang D Lu Gang G Loomes Kerry M KM Chan Wai-Yee WY Liu Xingguo X

Nature communications 20240116 1

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 burd ...[more]

PMID: 38228611

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Project description:BackgroundMitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNAAsn have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNAAsn variants.MethodsSix patients (from four families) carrying mt-tRNAAsn variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNAAsn variants was evaluated.ResultsThe variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNAAsn. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNAAsn, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species.ConclusionsThe study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNAAsn variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNAAsn and rescue mitochondrial dysfunction caused by mt-tRNAAsn variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNAAsn variants.

Dataset Information

NAD⁺ dependent UPR^mt activation underlies intestinal aging caused by mitochondrial DNA mutations.

Publications

NAD<sup>+</sup> dependent UPR<sup>mt</sup> activation underlies intestinal aging caused by mitochondrial DNA mutations.

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Dataset Information

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

Publications

NAD<sup>+</sup> dependent UPR<sup>mt</sup> activation underlies intestinal aging caused by mitochondrial DNA mutations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

NAD⁺ dependent UPR^mt activation underlies intestinal aging caused by mitochondrial DNA mutations.