α‐ketoglutarate delays age‐related fertility decline in mammals

Zhang, Zhenzhen; He, Chao; Gao, Yu; Zhang, Lu; Song, Yukun; Zhu, Tianqi; Zhu, Kuanfeng; Lv, Dongying; Wang, Jing; Tian, Xiaoli; Ma, Teng; Ji, Pengyun; Cui, Wei; Liu, Guoshi

doi:10.1111/acel.13291

Cited by 39 publications

(29 citation statements)

References 44 publications

(57 reference statements)

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“…We also identified a number of glucose derivatives and tricarboxylic acid (TCA) cycle intermediates or derivatives as well as fatty acids, the steroid ester cholesterol sulfate, and the nucleoside uridine. The majority of the metabolites identified in this study have been previously identified in the follicular fluid of cattle, humans, pigs, sheep, and horses [ 26 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. To our knowledge, the metabolites N-acetyl-beta-alanine, O -acetyl-l-serine, 2-oxo-4-methylthiobutanoate, 3-methylphenylacetic acid, phenyllactic acid, N-acetylornithine, tricarbalylic acid, 2-dehydro-D-gluconate, and D-gluconate are more novel components of the mammalian follicular fluid metabolome.…”

Section: Resultsmentioning

confidence: 99%

Correlation between Pre-Ovulatory Follicle Diameter and Follicular Fluid Metabolome Profiles in Lactating Beef Cows

et al. 2021

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Induced ovulation of small pre-ovulatory follicles reduced pregnancy rates, embryo survival, day seven embryo quality, and successful embryo cleavage in beef cows undergoing fixed-time artificial insemination. RNA-sequencing of oocytes and associated cumulus cells collected from pre-ovulatory follicles 23 h after gonadotropin-releasing hormone (GnRH) administration to induce the pre-ovulatory gonadotropin surge suggested reduced capacity for glucose metabolism in cumulus cells of follicles ≤11.7 mm. We hypothesized that the follicular fluid metabolome influences metabolic capacity of the cumulus-oocyte complex and contributes to reduced embryo cleavage and quality grade observed following induced ovulation of small follicles. Therefore, we performed a study to determine the correlation between pre-ovulatory follicle diameter and follicular fluid metabolome profiles in lactating beef cows (Angus, n = 130). We synchronized the development of a pre-ovulatory follicle and collected the follicular contents approximately 20 h after GnRH administration. We then performed ultra-high performance liquid chromatography—high resolution mass spectrometry (UHPLC-HRMS) metabolomic studies on 43 follicular fluid samples and identified 38 metabolites within pre-ovulatory follicles of increasing size. We detected 18 metabolites with a significant, positive correlation to follicle diameter. Individual and pathway enrichment analysis of significantly correlated metabolites suggest that altered glucose and amino acid metabolism likely contribute to reduced developmental competence of oocytes when small pre-ovulatory follicles undergo induced ovulation.

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Section: Resultsmentioning

confidence: 99%

Correlation between Pre-Ovulatory Follicle Diameter and Follicular Fluid Metabolome Profiles in Lactating Beef Cows

et al. 2021

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“…AKG is an important intermediate in the TCA cycle, impacts ATP production as a key point in the anaplerotic pathway [ 7 , 15 , 46 , 47 ], involved in the biosynthesis of proteins and amino acids [ 48 ] as a substrate of amino acid transferase and glutamate dehydrogenase, and influences epigenetic regulation in ageing [ 7 , 19 , 20 ]and metabolism [ 8 , 49 ] as an obligate substrate of histone and DNA demethylases [ 15 , 50 ]. Exogenous AKG also affects the cellular energy supply under the effects of various adverse factors [ 14 , [51] , [52] , [53] ], such as bacterial endotoxins and hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…AKG is an essential cofactor and substrate for many biological enzymes, including hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) and the histone demethylases JMJDs and ten-eleven translocation hydroxylases (TET1-3), which are involved in DNA demethylation [ 15 ], and participates in multiple cellular metabolic and regulatory pathways. Growing evidence suggests that AKG has protective effects, such as its ability to regulate metabolism [ 16 ], promote autophagy [ 17 ], reduce inflammation [ 18 ], delay ageing [ 19 , 20 ] and extend life span [ 21 ]. Although previous studies showed the association between a high circulating AKG level with HF severity and short-term adverse outcome in HF patients, there have been fewer relevant studies on the effects of AKG in HF.…”

Section: Introductionmentioning

confidence: 99%

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice

Zeng

Zhang

et al. 2021

Redox Biology

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Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of β-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

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“…The study demonstrates the importance of α-KG on reproductive aging in mammals including mice, pigs, and humans [43], and we think α-KG supplementation improves meiotic maturation of porcine oocytes and promotes the development of PA embryos by activating cellular antioxidant response mechanisms.…”

Section: Discussionmentioning

confidence: 61%

α-Ketoglutarate Improves Meiotic Maturation of Porcine Oocytes and Promotes the Development of PA Embryos, Potentially by Reducing Oxidative Stress through the Nrf2 Pathway

Chen

Gao

et al. 2022

Oxidative Medicine and Cellular Longevity

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α-Ketoglutarate (α-KG) is a metabolite in the tricarboxylic acid cycle. It has a strong antioxidant function and can effectively prevent oxidative damage. Previous studies have shown that α-KG exists in porcine follicles, and its content gradually increases as the follicles grow and mature. However, the potential mechanism of supplementation of α-KG on porcine oocytes during in vitro maturation (IVM) has not yet been reported. The purpose of this study was to explore the effect of α-KG on the early embryonic development of pigs and the mechanisms underlying these effects. We found that α-KG can enhance the development of early pig embryos. Adding 20 μM α-KG to the in vitro culture medium significantly increased the rate of blastocyst formation and the total cell number. Compared with to that of the control group, apoptosis in blastocysts of the supplement group was significantly reduced. α-KG reduced the production of reactive oxygen species and glutathione levels in cells. α-KG not only improved the activity of mitochondria but also inhibited the occurrence of apoptosis. After supplementation with α-KG, pig embryo pluripotency-related genes (OCT4, NANOG, and SOX2) and antiapoptotic genes (Bcl2) were upregulated. In terms of mechanism, α-KG activates the Nrf2/ARE signaling pathway to regulate the expression of antioxidant-related targets, thus combating oxidative stress during the in vitro culture of oocytes. Activated Nrf2 promotes the transcription of Bcl2 genes and inhibits cell apoptosis. These results indicate that α-KG supplements have a beneficial effect on IVM by regulating oxidative stress during the IVM of porcine oocytes and can be used as a potential antioxidant for IVM of porcine oocytes.

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α‐ketoglutarate delays age‐related fertility decline in mammals

Cited by 39 publications

References 44 publications

Correlation between Pre-Ovulatory Follicle Diameter and Follicular Fluid Metabolome Profiles in Lactating Beef Cows

Correlation between Pre-Ovulatory Follicle Diameter and Follicular Fluid Metabolome Profiles in Lactating Beef Cows

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice

α-Ketoglutarate Improves Meiotic Maturation of Porcine Oocytes and Promotes the Development of PA Embryos, Potentially by Reducing Oxidative Stress through the Nrf2 Pathway

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