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Deletion of enzymes for de novo NAD⁺ biosynthesis accelerated ovarian aging.

ABSTRACT: Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD⁺ ) in ovarian aging. However, the roles of de novo NAD⁺ biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD⁺ biosynthesis, resulted in decreased ovarian NAD⁺ levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD⁺ booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD⁺ de novo pathway in middle-aged female fertility.

SUBMITTER: Yang Q

PROVIDER: S-EPMC10497836 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Deletion of enzymes for de novo NAD+ biosynthesis accelerated ovarian aging.

Yang Qingling Q Li Hui H Wang Huan H Chen Wenhui W Zeng Xinxin X Luo Xiaoyan X Xu Jianmin J Sun Yingpu Y

Aging cell 20230618 9

Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD+ ) in ovarian aging. However, the roles of de novo NAD+ biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD+ biosynthesis, resulted in decreased ovarian NAD+ levels in middle-aged mice, leading to subfertility, ir ...[more]

PMID: 37332134

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Project description:BackgroundInflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation.MethodsTranscriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice.ResultsTryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation.ConclusionThe results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

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Deletion of enzymes for de novo NAD⁺ biosynthesis accelerated ovarian aging.

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Deletion of enzymes for de novo NAD<sup>+</sup> biosynthesis accelerated ovarian aging.

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