Abstract
In brief
Alpha-ketoglutarate is a common metabolite in the tricarboxylic acid cycle and is central in modulating the reproductive potential in animal models. The present scoping review systematically covers the spectrum of a wide range of evidence from different viewpoints, focusing on the underlying processes and mechanisms of the developmental framework, aiming to fill the gaps within the existing literature.
Abstract
Alpha-ketoglutarate is an important intermediate molecule in the tricarboxylic acid cycle with a prominent role in distinct biological processes such as cellular energy metabolism, epigenetic regulation, and signaling pathways. We conducted a registered scoping review (OSF: osf.io/b8nyt) to explore the impact of exogenous supplementation on reproductive capabilities. Our strategy included evaluating the main research literature from different databases like PubMed-MEDLINE, Web of ScienceTM, Scopus, and Excerpta Medica dataBASE using a specific systematic layout to encompass all investigations based on experimental models and critically compare the results. Twenty-one studies were included in the main body of this manuscript, which revealed that exogenous supplementation induced dose- and sex-dependent modifications. This metabolite modulates the expression of pluripotency genes, thus controlling stem cells’ self-renewal, differentiation, and reprogramming dynamics, while also alleviating structural transformations induced by exposure to heavy metals and other inhibitors. This significantly demonstrated a direct influence of alpha-ketoglutarate in mitigating oxidative stress and prolonging the lifespan, consequently supporting metabolic and endocrine adjustments. It influences oocyte quality and quantity, delays reproductive aging, and establishes an optimal competence framework for development with minimal risk of failure. Therefore, alpha-ketoglutarate is linked to improving reproductive performance, but further studies are needed due to a lack of studies on humans.
Introduction
Alpha-ketoglutarate (α-KG) is an essential intermediate metabolite in the tricarboxylic acid (TCA) cycle, also regarded as the Krebs or citric acid cycle (Harrison & Pierzynowski 2008, Wu et al. 2016). This endogenous α-ketoglutaric acid anion actively participates as a factor in fundamental biological processes linked to cellular energy metabolism, epigenetic regulation, and signaling pathways (Zdzisińska et al. 2017, Legendre et al. 2020). α-KG may be formed and dissociated through several pathways: (I) isocitrate oxidative decarboxylation, catalyzed by isocitrate dehydrogenase (IDH), (II) oxidative deamination of glutamate (Glu) via glutamate dehydrogenase (GLDH) (III) or decarboxylation to succinyl-coenzyme A (CoA) and carbon dioxide (CO2) by α-KG dehydrogenase (Wu et al. 2016, Zdzisińska et al. 2017, Liu et al. 2018a, Legendre et al. 2020).
Studies have demonstrated that physiological impairments are directly correlated with age, marked by a decline in the quality and quantity of oocytes (te Velde & Pearson 2002) complementary to the excess of free radicals assembling (Guimarães et al. 2021). Subsidiary investigations recommended incorporating α-KG into the dietary routine (Velvizhi et al. 2002, Jiang et al. 2017) to retard aging (Demidenko et al. 2021) as a viable alternative to prolong life’s longevity and health (Asadi Shahmirzadi et al. 2020).
The intricate interplay between energy metabolism and cell signaling pathways has been thoroughly substantiated (Wu et al. 2016, Liu et al. 2018a, Legendre et al. 2020). Therefore, exogenous supplementation might strengthen the antioxidant defenses against reactive oxygen species (ROS) via decarboxylation (Mailloux et al. 2009, Bignucolo et al. 2013, Aldarini et al. 2017). Besides its scavenger effect (Song et al. 2016, Wu et al. 2019) to avert premature aging (Goud et al. 2008, Lord & Aitken 2013, Sasaki et al. 2019), α-KG maintains the integrity of DNA, regulates autophagy and apoptosis (Satpute et al. 2010, Gibson et al. 2012, An et al. 2021, Qin et al. 2021), and alleviates inflammatory reactions and abnormal immune responses (Liu et al. 2018b). Available data highlighted the reliability of α-KG for reproductive disturbances based on the numerous applications that targeted ROS’ elevated ratio consequences on a molecular and morphological level in affected oocytes and on altered mitochondria (Zhang et al. 2019a, Yang et al. 2020). Conversely, the current state of knowledge enabled applications on abnormal morphology and early embryonic development decline (Zhang et al. 2019a,b, Miao et al. 2020) or correlated with depletion (Balaban & Urman 2006, Miao et al. 2009).
These structural transformations might have multiple negative outcomes that range from a heightened risk of aneuploidy (Mikwar et al. 2020) or miscarriage (Santonocito et al. 2013, Capalbo et al. 2017), to reduced testosterone secretion, spermatogenesis, and sperm motility and morphology abnormalities (Harris et al. 2011). Despite controversies over the passive influence of metabolism in embryogenesis, cell fate, and signal transduction (Wu et al. 2016, Zdzisińska et al. 2017, Legendre et al. 2020), recent discoveries promoted advances dedicated to containing oocyte rate decrease (Lord & Aitken 2013, Zhang et al. 2019a,b) caused by telomere shortening (Broekmans et al. 2009).
Therefore, this scoping review aims to provide an updated perspective on the latest applications to reconfigure reproductive capacity. The need for this manuscript derives from the limited settings compared to other research directions (Meng et al. 2022, Naeini et al. 2023). Conclusively, the main objective is to open possible new therapeutic approaches and translate gained information into clinical practice.
Materials and methods
Methodology and registration
The protocol of this manuscript was designed to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2018 guidelines for Scoping Review (PRISMA-ScR) (Munn et al. 2018, Tricco et al. 2018) and was registered in the Open Science Framework (OSF) with the ID: osf.io/b8nyt (https://doi.org/10.17605/OSF.IO/YT3BA).
Ethics committee
This manuscript did not require Institutional Review Board (IRB) approval, signed consent forms, or a third-party evaluation because data was extracted from published studies.
Objectives
We hypothesized that adequate supplementation with α-KG may improve the ability of the reproductive system, similar to its involvement in extending the lifespan and reversing oxidative stress (OS) following the normalization of ROS.
Research questions
Primary question
Does the supplementation with α-KG enhance reproduction in experimental laboratory models?
Secondary questions
Does the supplementation with α-KG prevent OS by normalizing the ROS levels?
Does the supplementation with α-KG extend the lifespan?
Source databases
We conducted searches to encompass the latest critical literature from January 1, 2010, to March 1, 2024, by accessing primary electronic academic databases: PubMed-MEDLINE—United States National Library of Medicine (NLM, 1996), Web of ScienceTM (WOS) (Clarivate Analytics, 1997), Scopus (Elsevier, 2004) (Falagas et al. 2008), and Excerpta Medica dataBASE (EMBASE) (Elsevier, 1947) (accessed on March 8, 2024).
Search strings
We applied dedicated and controlled scientific terminology using MeSH (Medical Subject Headings), Boolean operators (‘AND’ or ‘OR’ or ‘NOT’), and Emtree terms. This approach was meant to ensure comprehensive coverage of relevant research articles before undergoing the identification, collection, ranking, and analysis steps. Several main input terms such as ‘α-ketoglutaric acid,’ ‘alpha-ketoglutaric acid,’ ‘2-ketoglutaric acid,’ ‘2-oxoglutaric acid,’ ‘oxoglutaric acid,’ and ‘2-oxopentanedioic acid,’ excepting ‘AKG’ and ‘2-oxoglutamate,’ were appointed as (Major Topic) with the MeSH Unique ID: D007656, Tree Number(s): D02.241.081.337.351.502, D02.241.755.465 and applied for distinct fields. The primary subtopics included ‘reproductive system’ (‘Genitalia’ (MeSH) – ID: D005835, Tree Number(s): A05.360), ‘fertility’ (‘Fertility’ (MeSH) – ID: D005298, Tree Number(s): G08.686.210), and ‘reproduction’ (‘Reproduction’ (MeSH) – ID: D012098, Tree Number(s): G08.686.784) in parallel with ‘laboratory model’ (‘Models, Animal’ (MeSH) – ID: D023421, Tree Number(s): E05.598) and ‘experimental animal’ (‘Animals, Laboratory’ (MeSH) – ID: D000830, Tree Number(s): B01.050.050.199) as found on the NLM official website (accessed on March 8, 2024). The complete strings for each database can be found in Supplementary File 1 (see section on supplementary materials given at the end of this article).
Study selection
The references list was subsequently imported to Mendeley – Reference Management Software (v. 1.19.8) (Elsevier, 2013) and de-duplicated using the ‘check for duplicates’ function followed by additional manual screening. Each investigator independently reviewed the titles ± abstracts of individual retrieved records. Afterward, BD, O-DI, A-MD, I-SS, and RM assessed the abstracts and the full-length content of each qualifying article. Possible conflicting opinions were settled unanimously by common consent with BD, ST, and ET.
Extraction of data
General data from the retrieved studies were organized in a tabular standardized form using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) by BD, O-DI, A-MD, I-SS, and RM that included methodological characteristics such as experimental model/cell line, compound, concentration, supplementation method, and main observations.
Criteria of inclusion and exclusion
Research had to be written exclusively in English and contain original data obtained from experiments carried out on experimental laboratory models. A particular eligibility requirement was that the studies had to include models with genetic similarity comparable to humans for clinical relevance or cell cultures to deepen the understanding of the underlying mechanisms further. Any other type of manuscript was automatically removed.
Results
Number of results and final inclusion
A total of 1606 studies were returned in the pre-determined timeframe, of which 947 (58.96%) were from PubMed-MEDLINE, 354 (22.04%) from WOSTM, 301 (18.74%) from EMBASE, and four (0.24%) from Scopus (Supplementary File 2) (accessed on March 8, 2024). By removing 1544 studies that did not undergo review, 62 studies remained, of which 31 preliminary eligible papers were retained, excluding duplicates. Furthermore, ten articles were removed in the second step due to the following reasons: one was an article written in Russian (Lucenko et al. 2016), two were out of scope (Willenborg et al. 2009, Mariño et al. 2014), two were eligible but the full content could not be accessed (Zhang et al. 2019a, Penn et al. 2023) and five had no direct correlation (Pedroso et al. 2019, Dobrowolski et al. 2021, Sekita et al. 2021, Tanaka et al. 2021, Shibata et al. 2024) (Fig. 1). Therefore, in the 21 studies that met the eligibility criteria, one was conducted on ovine (Hao et al. 2022), two on porcine (Breininger et al. 2014, Chen et al. 2022), four on Drosophila melanogaster (Bayliak et al. 2017, 2019, Lylyk et al. 2018, Su et al. 2019), and 14 on murine models: two on mice (Zhang et al. 2021, Wang et al. 2023), three on rats (Li et al. 2010, 2023, Liu et al. 2024) and nine on stem cells that investigated the pluripotency, differentiation, or reprogramming modifications in standard or transgenic lines (Carey et al. 2015, Hwang et al. 2016, TeSlaa et al. 2016, Choi et al. 2019, Tischler et al. 2019, Xing et al. 2020, Xu et al. 2022, Yang et al. 2022, Tang et al. 2023) (Supplementary Table 1).
Study features
Half of the studies were conducted exclusively by researchers from China (50%) (Li et al. 2010, 2023, Su et al. 2019, Xing et al. 2020, Chen et al. 2022, Hao et al. 2022, Yang et al. 2022, Xu et al. 2022, Tang et al. 2023, Wang et al. 2023, Liu et al. 2024), Japan (9.09%) (Choi et al. 2019, Tanaka et al. 2021), USA (9.09%) (Carey et al. 2015, TeSlaa et al. 2016) Argentina (4.54%) (Breininger et al. 2014), Republic of Korea (4.54%) (Hwang et al. 2016) or multidisciplinary teams from Ukraine and Canada (13.63%) (Bayliak et al. 2017, 2019, Lylyk et al. 2018), United Kingdom and Germany (4.54%) (Tischler et al. 2019) or with double affiliations from China and United Kingdom (4.54%) (Zhang et al. 2021). The reiterative lists of each assessment phase can be found in Supplementary File 3.
Stem cell pluripotency and differentiation
Although the connection between cellular metabolism and cell differentiation has been recently addressed, auxiliary research uncovered the potential of self-renewal and differentiation (Carey et al. 2015, Hwang et al. 2016, TeSlaa et al. 2016, Tischler et al. 2019, Xing et al. 2020, Yang et al. 2022, Tang et al. 2023). Naïve mESCs preserve their pluripotency until reaching the PGCs state (Tischler et al. 2019) even in the absence of Gln (Carey et al. 2015). In this context, supplementation with α-KG concomitantly with glucose or pyruvate sustains the Gln-Glu-α-KG axis to support maternal decidualization (Tang et al. 2023), blastocyst formation (Choi et al. 2019), and the amount of intracellular α-KG (Carey et al. 2015) through the IDH2-mediated production (Tischler et al. 2019). α-KG delays aging and heat shock-induced changes upon sperm via OXGR1 expressed in epididymal SMCs (Xu et al. 2022), and restores Gln-Glu flux metabolism (Tang et al. 2023). Several remarks underlined the inhibition of the BPTES effect on PGCLC (Xing et al. 2020) which translates into the number and function of dNK (Yang et al. 2022) that ultimately may reduce the risk of induced pregnancy (Yang et al. 2022) and spontaneous miscarriage (Tang et al. 2023). Naïve mESCs store α-KG/succinate (Carey et al. 2015), which is regulated by Psat1 (Hwang et al. 2016) and required for primed PSCs acceleration (TeSlaa et al. 2016) and epigenetic reprogramming (Carey et al. 2015, Hwang et al. 2016, TeSlaa et al. 2016). Psat1 KD is thought to be the cause of reduced mESCs DNA 5’-hydroxymethylcytosine (5’-hmC) methylation (Hwang et al. 2016), influencing the ATP generation mechanism (TeSlaa et al. 2016, Tang et al. 2023) and H3K27me3-based chromatin modifications and ten-eleven translocation (TET)-dependent DNA demethylation process (Carey et al. 2015, Hwang et al. 2016, TeSlaa et al. 2016, Tischler et al. 2019, Xing et al. 2020, Yang et al. 2022, Tang et al. 2023).
Rodents
While higher mammals are subjected to reproductive aging mainly because of telomere shortening (Zhang et al. 2021), controlled concentrations of α-KG might delay the decline in ovarian reserve (Li et al. 2023, Wang et al. 2023), and loss of function (Zhang et al. 2021, Liu et al. 2024). This metabolite triggers adaptations of metabolism and consequent variations in levels of hormones (Li et al. 2023, Liu et al. 2024), linked to reproductive function reconfiguration (Zhang et al. 2021) even in aging oocytes post-ovulation (Wang et al. 2023). α-KG inhibits the mTOR pathway by blocking ATP synthase (Zhang et al. 2021), thus contradicting previous studies showing higher ATP levels (Li et al. 2023) due to enhanced mitochondrial membrane potential (Wang et al. 2023). Although the level of pyruvate in females is reduced (Li et al. 2023) unlike males who experience an increase in O2-. level in sperm, this does not always have negative effects (Liu et al. 2024) since both are pivotal in sustaining spermatozoa ATP levels for motility (Li et al. 2010). These antioxidants are involved in diminishing ROS levels, which thus mitigates the pro-inflammatory cascade (Liu et al. 2024), resulting in a lower rate of fragmentation, abnormal spindle assembly (Wang et al. 2023), and apoptosis (Li et al. 2023).
Flies
Drosophila melanogaster is a genetic model broadly employed for deepening our awareness of the reproduction paradigm (Bayliak et al. 2017, Lylyk et al. 2018, Su et al. 2019) and the consequences of heavy metals exposure (Bayliak et al. 2019). α-KG diet supplementation leads to fluctuations in metabolic parameters dependent on the developmental stage (Bayliak et al. 2017) and effectively alleviates AlCl3 toxicity (Bayliak et al. 2019). The extended lifespan seen at specific concentrations is dose- and sex-dependent (Lylyk et al. 2018, Bayliak et al. 2019, Su et al. 2019), but higher doses can be harmful, especially in males (Lylyk et al. 2018). This does not exacerbate the OS but triggers adaptive responses instead (Bayliak et al. 2017, 2019, Lylyk et al. 2018, Su et al. 2019) due to decreased ATP/ADP ratio (Su et al. 2019). This might clarify the heightened tolerance to heat stress (Bayliak et al. 2017, 2019), upregulation of the mRNA expression of protein genes involved in longevity (Su et al. 2019), and decreased fecundity (Bayliak et al. 2017, 2019, Lylyk et al. 2018, Su et al. 2019), while remarkably enhancing the egg-laying capacity in AlCl3-reared flies (Bayliak et al. 2019).
Porcine
Research indicates that α-KG is a potent scavenger of free radicals in porcine, as it significantly reduces ROS generation required for the biosynthesis of GSH. The NRF2/ARE pathway facilitates the transcription of apoptotic genes and enhances mitochondrial function by activating NRF2, thus preventing a biased process of apoptosis (Chen et al. 2022). α-KG promotes an optimal framework for pig embryo development through the upregulation of pluripotency genes, leading to the formation of blastocysts and the total cell number during in vitro maturation (IVM) (Chen et al. 2022). Nonetheless, the addition in the culture medium of phosphofructokinase (PFK) and malate dehydrogenase (MDH) can hinder the nutritional requirements of cumulus-oocyte complex (COC) during IVM and cause dysfunction of meiotic maturation (Breininger et al. 2014).
Ovine
In contrast to results from the fruit flies, dm-α-KG was found to induce comparable phenotypical features as seen in porcine, notably an increased ATP synthesis based on enhanced mitochondrial activity and GSH production against pro-oxidants. dm-α-KG relieves abnormal ROS generation, which could potentially degrade the integrity of the DNA, alter mitochondria, and trigger apoptosis. Therefore, dm-α-KG showed promising activity in maintaining nuclear maturation rate, CGs dynamic, and embryonic developmental competence (Hao et al. 2022).
Discussion
α-KG is a source of ATP in all living organisms’ cells (He et al. 2015) and is predominantly found in mitochondria and cytosol (Fig. 2) besides the bloodstream (Wagner et al. 2010). Previous experiments on animal models demonstrated high versatility (Niemiec et al. 2011, Radzki et al. 2012, 2015, Wang et al. 2015, Cai et al. 2018) in various organs such as the brain, heart, liver, gastrointestinal tract, skeletal muscle, and adipose tissue (He et al. 2015). It has been proven to modulate the molecular landscape via the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) (He et al. 2015), and even hypothesized to interact with calcium/calmodulin-dependent protein kinase kinase 2 (CamKK2) (Jin et al. 2018).
Schematic overview of mitochondrial metabolism of pyruvate and glutamine in the TCA cycle. Amino acids-derived glucose is subjected to sequential phases of conversion that facilitate the production of α-KG through either glycolysis or glutaminolysis. The final fatty acids are produced by blocking the oxidative pathway and enhancing the reductive pathway. The AMPK and mTOR signaling pathways control the α-KG level when the ratio of AMP/ATP is high, thus regulating autophagy. GLUT1/4 – glucose transporter type 1/4, MPC – mitochondrial pyruvate carrier, PDH – pyruvate dehydrogenase, PC – pyruvate carboxylase, IDH – isocitrate dehydrogenase, α-KGDH – α-KG dehydrogenase, GLS – glutaminase, GDH – glutamate dehydrogenase.
Citation: Reproduction 168, 5; 10.1530/REP-24-0137
mTOR is part of a conserved group of serine/threonine (Ser/Thr) protein kinases of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, comprising rapamycin-sensitive complex 1 (mTORC1) and relatively rapamycin-insensitive complex 2 (mTORC2). Both play a role in growth and metabolism, primarily found in the nucleus and cytoplasm (Saxton & Sabatini 2017, Jhanwar-Uniyal et al. 2019), while AMPK serves as a key energy sensor in aging and lifespan (Hardie et al. 2012, Huang et al. 2013), collectively promoting lysosomal translocation through mTORC1 known to block autophagy (Durán et al. 2012).
The initial data on Caenorhabditis elegans’ increased lifespan from inhibiting ATP synthase and phosphor-Akt (Shrimali et al. 2021), as well as the mTOR signaling pathway (Hou et al. 2010, Żurek et al. 2019) by α-KG in a dose-dependent manner, was founded a decade ago (Chin et al. 2014). Noteworthy, α-KG longevity partially depends on AMPK and the forkhead box O (FOXO) (Urban et al. 2007) as already seen in flies (Kapahi et al. 2004, Luong et al. 2006, Su et al. 2019) and mice (Selman et al. 2009).
It is important to note that AMPK activates when the AMP/ATP ratio is high and hampers TOR signaling by phosphorylation of the TOR suppressor tuberous sclerosis complex (TSC) 1, which regulates cell energy rate and metabolism (Toivonen et al. 2007). α-KGs activate mTOR in the intestinal epithelial cells of pigs to stimulate protein (Yao et al. 2012) or milk protein synthesis (Jiang et al. 2016).
α-KG can increase the FOXO mRNA expression (Su et al. 2019), a transcription factor that helps maintain the cytosolic level of α-KG (Charitou et al. 2015) by regulating isocitrate dehydrogenase 1 (IDH1). Prolyl hydroxylase domain protein (PHD) catalyzes proline hydroxylation and facilitates FOXO3 degradation. A possible reduction of α-KG in hypoxic tubules instead stabilizes FOXO3 to augment autophagy (Tran et al. 2019).
Biological aging involves a high degree of epigenetic changes (Shi & Whetstine 2007, Walport et al. 2012, Salminen et al. 2015, Martínez-Reyes & Chandel 2020), that implicitly lead to hypermethylation of specific DNA regions and histone patterns (Gonzalo, 2010, Sierra et al. 2015). Despite the recent progress in translational medicine (Xiao et al. 2016, Gyanwali et al. 2022, Naeini et al. 2023), the clinical validation of α-KG as a feed additive is still lacking as existing data only includes experiments conducted in animal models. Nonetheless, direct oral supplementation may be a feasible method to address a deficiency as demonstrated by (Demidenko et al. 2021) who successfully reduced the average biological aging by eight years in both sexes following Rejuvant® tablets for seven months (P = 6.538x10-12). 2-oxoglutarate, regarded as α-KG, along with other Krebs cycle analogs succinate, fumarate, and 2-hydroxyglutarate (2-HG) are integral to mitochondrial metabolism and influence DNA and histone methylation (Ward & Thompson 2012, Badeaux & Shi 2013, Kaelin & McKnight 2013, Salminen et al. 2014a , b ). These essential epigenetic regulators of gene expression are part of the 2-oxoglutarate-dependent dioxygenases (2-OGDDs) family, known for their involvement in demethylation and hydroxylation processes (McDonough et al. 2010, Loenarz & Schofield 2011) which might shape chromatin structure and function (Ward & Thompson 2012, Badeaux & Shi 2013, Kaelin & McKnight 2013).
Precisely, hydroxylases TET1-3 are DNA demethylases that catalyze the oxidative decarboxylation of α-KG to convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and trigger demethylation of CpG loci in DNA (Tahiliani et al. 2009, Ito et al. 2010, Salminen et al. 2015). Similarly, histone demethylases containing Jumonji C domain lysine KDM2-7 contribute to the regulation of chromatin landscape changes associated with aging (Shi & Whetstine 2007, Walport et al. 2012, Salminen et al. 2015). As a result, they are accountable for removing methyl groups from specific methylation sites in histones, a process that also catalyzes the demethylation of trimethylated lysines and arginines (Hoffmann et al. 2012), crucial for forming both transcriptionally active and inactive chromatin (Shi & Whetstine 2007, Gonzalo 2010, Walport et al. 2012).
Data from cancer research showed that succinate and fumarate could act as competitive inhibitors of the 2-OGDO enzymes, precisely KDMs and TETs, which potentiate methylation of DNA and histones by methyltransferases, ultimately causing carcinogenesis (Ward & Thompson 2012, Kaelin & McKnight 2013, Martínez-Reyes & Chandel 2020). Considering the extensive work of (Salminen et al. 2014a , b , 2015) on the topics discussed earlier, the role of KDM2/6 in gene expression and cell fate is rather complex as it involves both inducing (Agherbi et al. 2009, Perrigue et al. 2015) and inhibiting senescence (Pfau et al. 2008) through the cell cycle arrest mediators p53 and pRb (Leon & Aird 2019).
In conclusion, chronic inflammation could be caused by enhanced cellular senescence leading to premature aging (Agherbi et al. 2009, Perrigue et al. 2015, Salminen et al. 2015), while histone demethylases containing Jumonji C domain lysine up-regulation are linked to cancer progression by blocking senescence (Pfau et al. 2008, Wang et al. 2018, Leon & Aird 2019).
Understanding the reproduction phenomenon to counter the decrease in quality and quantity of oocytes (te Velde & Pearson 2002) is mandatory, especially in conjunction with early embryonic potential (Zhang et al. 2019a , b , Miao et al. 2020), to reduce the risk of aneuploidy (Mikwar et al. 2020) and miscarriage (Santonocito et al. 2013, Capalbo et al. 2017) in light of the numerous applications targeting aged oocytes (Miao et al. 2009, Yamada-Fukunaga et al. 2013, Garcia et al. 2019). The telomerase complex, which consists of Terc and the catalytic subunit Tert, plays a compensatory role in slowing aging by supporting the maintenance of the telomere system along with SIRT6 (Tennen et al. 2011), as well as performing important roles in DNA repair and inflammation (You & Liang 2023).
In the urge for an effective antioxidant against ROS, which is seen as the main forerunner of decreased quality of aged oocytes (Lord & Aitken 2013, Sasaki et al. 2019), α-KG has emerged as the key factor in refining the antioxidant defense system (Velvizhi et al. 2002) that is also responsible for removing H2O2 by decarboxylation (Aldarini et al. 2017). However, α-KG via the Nrf2 pathway in adequate concentrations counteracts the impact of brutasol and partially restores metal content balance (Orgad et al. 1998, Wu et al. 2012, Fu et al. 2014, Maya et al. 2016) after a 26% increase of aconitase (Middaugh et al. 2005, Wu et al. 2012) to support embryonic development and shield oocytes from OS (Jiang et al. 2021). An elevated intracellular level of GSH (Brigelius-Flohé, 1999, de Matos & Furnus 2000, Liu et al. 2018a ) prevents DNA damage and cell death (Jia et al. 2018, Zhou et al. 2019, Chen et al. 2020, Aghaz et al. 2021, El-Sheikh et al. 2021, Min et al. 2021), indicating an ideal framework for developmental competence (Ren et al. 2021). Alternatively, α-KG may influence the PFK and MDH-related COC role on oocyte maturation in bovine (Cetica et al. 2002, 2003), and porcine (Breininger et al. 2014) as previously suggested, owing that a preliminary investigation that revealed the presence of IDH-nicotinamide adenine dinucleotide (NAD) in porcine COC but not in cows (Cetica et al. 2003).
According to the available information regarding α-KG’s potential to sustain both naïve and primed PSCs’ pluripotency and differentiation (Leitch et al. 2013), a biphasic concept of α-KG was proposed, modulated by the oxygen level apart from its position as a cofactor for DNA and histone demethylation (TeSlaa et al. 2016). The TET complex is a widely recognized mechanism in DNA demethylation known to participate in converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC) (TeSlaa et al. 2016). Maternal high-fat diet (MHFD) reduces 5-hmC DNA methylation while increasing 5-fC (Penn et al. 2023), hindering early-stage embryo development that depends on low ATP production and altered activity of DNA methyltransferase 3 alpha (Dnmt3a) and an elevated 5-hmC and 5-mC ratio (Zhang et al. 2019a). The ratio is notably elevated in PSCs compared to differentiated cells (Tran et al. 2019), thus confirming epigenetic reprogramming based on the TET-mediated conversion of 5-mC to 5-hmC (Sekita et al. 2021).
Studies have shown that Jumonji C-containing domains that reunite lysine demethylase 3-6A/3-6B (KDM3A/3B/6A/6B) (Ko et al. 2006, Loh et al. 2007) (JHDMs) require α-KG to target distinct histones (Klose & Zhang 2007). TET members methylcytosine dioxygenase 1 (TET1) and TET methylcytosine dioxygenase 2 (TET2) (Costa et al. 2013, Hackett & Surani 2014) can maintain the naïve pluripotency epigenetic state by demethylating H3K27me2/me3 (histone 3 lysine 27 methylation) (TeSlaa et al. 2016) given that low DNA demethylation levels may result in an increased spread of H3K27me3 at high CpG regions (Zylicz et al. 2015). α-KG could potentially preserve the naïve pluripotent status in PSCs when 2i inhibitors are substituted (Ying et al. 2008, Tischler et al. 2019) due to IDH-related high expression based on DNA methyltransferase 3 beta (DNMT3B) depletion. Some suggest that a re-wiring of 2i in culture conditions could support Gln-independent growth of naïve mESCs (Carey et al. 2015).
The switch from naïve mESCs to PGC-competent EpiLCs involves a change to a glycolytic state instead of oxidative (Zhou et al. 2012, Zhang et al. 2016) during later stages (Folmes et al. 2012) due to the upregulation of lin-28 homolog B (Lin28b). Lin28b is a protein-coding gene involved in oxidative suppression and regulation of glucose metabolism (Zhu et al. 2011, Zhang et al. 2016) as the metabolic modulator 2-DG is activated (Hayashi et al. 2017). Lactate shuttle (LS) and Warburg-like glycolysis participate during decidualization since DNA methylation is stable (Maekawa et al. 2019, Liu et al. 2020) and DNA hydroxylases TET are dioxygenases (Raffel et al. 2017) dependent on α-KG. As the bio-energetic requirements (Zuo et al. 2015, Huang et al. 2019, Tamura et al. 2021) are assured, supplementary resources for proliferation and differentiation are necessary despite higher glucose intake (Ying et al. 2021), these conditions under an aerobic state being met by Gln metabolism (Le et al. 2012, Li & Zhang 2016).
α-KG can also trigger primed PSCs differentiation by interacting with chaperone-mediated autophagy (CMA) (Xu et al. 2020), causing changes in the expression of transcription factors and being limited by the inhibitory effects of 3-nitropropionic acid (NPA). This reduction in succinate delays PSCs differentiation, but this effect is counteracted by TET2, which promotes differentiation (Hon et al. 2014, TeSlaa et al. 2016). Autophagy collaborates with the ubiquitin-proteasome system (UPS) to regulate protein levels linked to pluripotency and influences the self-renewal or differentiation of ESCs based on CMA level (Xu et al. 2020, Xu & Yang 2022).
SOX2 and OCT4 influence ESCs (Xu et al. 2020) through inhibition of lysosome-associated membrane protein type 2A (LAMP2A), a key component in parallel with cytosolic chaperone HSC70 that defines CMA activity (Cuervo & Dice 2000). Changes in LAMP2A levels correspond to levels of SOX2 and OCT4, and in what concerns differentiation, a possible depletion in mESCs indicates high levels of the α-KG/succinate ratio, whereas mESCs overexpression leads to a gradual decline of LAMP2A (Xu et al. 2020).
Finally, reprogramming has been a topic of interest on several occasions with special emphasis on TET in induced PSCs (iPSCs) from differentiated or non-pluripotent cells (Kolaczkowski & Thornton 2004, Polo et al. 2012, Sardina et al. 2018). AKT and FOXO1 signaling pathway activation or simultaneous transduction of TET2’s catalytic domain and dm-α-KG synergistically improve reprogramming (Sekita et al. 2021), relying on increased glycolysis and mitochondrial activity (Yu et al. 2014, Wilhelm et al. 2016).
Strengths and limitations of the study
This primary scoping review systematically approaches this scarce topic by including multiple databases to ensure a thorough and comparative overview without neglecting critical and authoritative information. However, it should be noted that the number of applications is limited to animal studies and even lower in humans, which is why clinical trials are mandatory, setting the grounds for future randomized controlled trials (RCTs).
Conclusions
The manuscript covers the importance of α-KG in maintaining the functionality and integrity of various biological mechanisms. Despite the research on animal models instead of humans, it is clear that α-KG supplementation improves reproductive abilities. However, additional experiments are needed to close the gap between research and clinical practice. This might result in treatment strategies and an improved understanding of the advantages of α-KG supplementation in humans.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/REP-24-0137.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.
Author contribution statement
Conceptualization, Data curation, Investigation, Formal analysis, Methodology, Software, Writing – original draft: BD, O-DI, A-MD, I-SS, and RM. Supervision, Visualization, Validation, Project administration, Writing – review and editing: BD, ST, and ET. All authors have read and agreed to the published version of the manuscript.
References
Aghaz F, Vaisi-Raygani A, Khazaei M, Arkan E & & Kashanian S 2021 Enhanced synergistic-antioxidant activity of melatonin and tretinoin by co-encapsulation into amphiphilic chitosan nanocarriers: during mice in vitro matured oocyte/morula-compact stage embryo culture model. Reproductive Sciences 28 3361–3379. (https://doi.org/10.1007/s43032-021-00670-8)
Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M & & Djabali M 2009 Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence. PLoS One 4 e5622. (https://doi.org/10.1371/journal.pone.0005622)
Aldarini N, Alhasawi AA, Thomas SC & & Appanna VD 2017 The role of glutamine synthetase in energy production and glutamine metabolism during oxidative stress. Antonie van Leeuwenhoek 110 629–639. (https://doi.org/10.1007/s10482-017-0829-3)
An D, Zeng Q, Zhang P, Ma Z, Zhang H, Liu Z, Li J, Ren H & & Xu D 2021 Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice. Redox Biology 46 102088. (https://doi.org/10.1016/j.redox.2021.102088)
Asadi Shahmirzadi A, Edgar D, Liao C-Y, Hsu Y-M, Lucanic M, Asadi Shahmirzadi A, Wiley CD, Gan G, Kim DE, Kasler HG, et al.2020 Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabolism 32 447–456.e6. (https://doi.org/10.1016/j.cmet.2020.08.004)
Badeaux AI & & Shi Y 2013 Emerging roles for chromatin as a signal integration and storage platform. Nature Reviews Molecular Cell Biology 14 211–224. (https://doi.org/10.1038/nrm3545)
Balaban B & & Urman B 2006 Effect of oocyte morphology on embryo development and implantation. Reproductive Biomedicine Online 12 608–615. (https://doi.org/10.1016/s1472-6483(1061187-x)
Bayliak MM, Lylyk MP, Shmihel HV, Sorochynska OM, Semchyshyn OI, Storey JM, Storey KB & & Lushchak VI 2017 Dietary alpha-ketoglutarate promotes higher protein and lower triacylglyceride levels and induces oxidative stress in larvae and young adults but not in middle-aged Drosophila melanogaster. Comparative Biochemistry and Physiology. Part A, Molecular and Integrative Physiology 204 28–39. (https://doi.org/10.1016/j.cbpa.2016.11.005)
Bayliak MM, Lylyk MP, Gospodaryov DV, Kotsyubynsky VO, Butenko NV, Storey KB & & Lushchak VI 2019 Protective effects of alpha-ketoglutarate against aluminum toxicity in Drosophila melanogaster. Comparative Biochemistry and Physiology. Toxicology and Pharmacology 217 41–53. (https://doi.org/10.1016/j.cbpc.2018.11.020)
Bignucolo A, Appanna VP, Thomas SC, Auger C, Han S, Omri A & & Appanna VD 2013 Hydrogen peroxide stress provokes a metabolic reprogramming in Pseudomonas fluorescens: enhanced production of pyruvate. Journal of Biotechnology 167 309–315. (https://doi.org/10.1016/j.jbiotec.2013.07.002)
Breininger E, Vecchi Galenda BE, Alvarez GM, Gutnisky C & & Cetica PD 2014 Phosphofructokinase and malate dehydrogenase participate in the in vitro maturation of porcine oocytes. Reproduction in Domestic Animals 49 1068–1073. (https://doi.org/10.1111/rda.12437)
Brigelius-Flohé R 1999 Tissue-specific functions of individual glutathione peroxidases. Free Radical Biology and Medicine 27 951–965. (https://doi.org/10.1016/s0891-5849(9900173-2)
Broekmans FJ, Soules MR & & Fauser BC 2009 Ovarian aging: mechanisms and clinical consequences. Endocrine Reviews 30 465–493. (https://doi.org/10.1210/er.2009-0006)
Cai X, Yuan Y, Liao Z, Xing K, Zhu C, Xu Y, Yu L, Wang L, Wang S, Zhu X, et al.2018 α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway. FASEB Journal 32 488–499. (https://doi.org/10.1096/fj.201700670R)
Capalbo A, Hoffmann ER, Cimadomo D, Ubaldi FM & & Rienzi L 2017 Human female meiosis revised: new insights into the mechanisms of chromosome segregation and aneuploidies from advanced genomics and time-lapse imaging. Human Reproduction Update 23 706–722. (https://doi.org/10.1093/humupd/dmx026)
Carey BW, Finley LWS, Cross JR, Allis CD & & Thompson CB 2015 Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518 413–416. (https://doi.org/10.1038/nature13981)
Cetica P, Pintos L, Dalvit G & & Beconi M 2002 Activity of key enzymes involved in glucose and triglyceride catabolism during bovine oocyte maturation in vitro. Reproduction (Cambridge, England) 124 675–681. (https://doi.org/10.1530/rep.0.1240675)
Cetica P, Pintos L, Dalvit G & & Beconi M 2003 Involvement of enzymes of amino acid metabolism and tricarboxylic acid cycle in bovine oocyte maturation in vitro. Reproduction (Cambridge, England) 126 753–763. (https://doi.org/10.1530/rep.0.1260753)
Charitou P, Rodriguez-Colman M, Gerrits J, van Triest M, Groot Koerkamp M, Hornsveld M, Holstege F, Verhoeven-Duif NM & & Burgering BMT 2015 FOXOs support the metabolic requirements of normal and tumor cells by promoting IDH1 expression. EMBO Reports 16 456–466. (https://doi.org/10.15252/embr.201439096)
Chen L, Zhang J-J, Zhang X, Liu X, Zhao S, Huo L-J, Zhou J & & Miao Y-L 2020 Melatonin protects against defects induced by Malathion during porcine oocyte maturation. Journal of Cellular Physiology 235 2836–2846. (https://doi.org/10.1002/jcp.29189)
Chen Q, Gao L, Li J, Yuan Y, Wang R, Tian Y & & Lei A 2022 α-Ketoglutarate improves meiotic maturation of porcine oocytes and promotes the development of PA embryos, potentially by reducing oxidative stress through the Nrf2 pathway. Oxidative Medicine and Cellular Longevity 2022 7113793. (https://doi.org/10.1155/2022/7113793)
Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, et al.2014 The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510 397–401. (https://doi.org/10.1038/nature13264)
Choi ES, Kawano K, Hiraya M, Matsukawa E & & Yamada M 2019 Effects of pyruvate and dimethyl-α-ketoglutarate, either alone or in combination, on pre- and post-implantation development of mouse zygotes cultured in vitro. Reproductive Medicine and Biology 18 405–410. (https://doi.org/10.1002/rmb2.12288)
Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S, et al.2013 NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495 370–374. (https://doi.org/10.1038/nature11925)
Cuervo AM & & Dice JF 2000 Regulation of lamp2a levels in the lysosomal membrane. Traffic (Copenhagen, Denmark) 1 570–583. (https://doi.org/10.1034/j.1600-0854.2000.010707.x)
de Matos DG & & Furnus CC 2000 The importance of having high glutathione (GSH) level after bovine in vitro maturation on embryo development effect of beta-mercaptoethanol, cysteine and cystine. Theriogenology 53 761–771. (https://doi.org/10.1016/S0093-691X(9900278-2)
Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK & & Budovskaya YV 2021 Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test. Aging 13 24485–24499. (https://doi.org/10.18632/aging.203736)
Dobrowolski P, Muszyński S, Donaldson J, Jakubczak A, Żmuda A, Taszkun I, Rycerz K, Mielnik-Błaszczak M, Kuc D & & Tomaszewska E 2021 The effects of prenatal supplementation with β-hydroxy-β-methylbutyrate and/or alpha-Ketoglutaric acid on the development and maturation of mink intestines are dependent on the number of pregnancies and the sex of the offspring. Animals : an Open Access Journal from MDPI 11. (https://doi.org/10.3390/ani11051468)
Durán RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E & & Hall MN 2012 Glutaminolysis activates Rag-mTORC1 signaling. Molecular Cell 47 349–358. (https://doi.org/10.1016/j.molcel.2012.05.043)
El-Sheikh M, Mesalam AA, Song S-H, Ko J & & Kong I-K 2021 Melatonin alleviates the toxicity of high nicotinamide concentrations in oocytes: potential interaction with nicotinamide methylation signaling. Oxidative Medicine and Cellular Longevity 2021 5573357. (https://doi.org/10.1155/2021/5573357)
Falagas ME, Pitsouni EI, Malietzis GA & & Pappas G 2008 Comparison of PubMed, Scopus, web of science, and google scholar: strengths and weaknesses. FASEB Journal 22 338–342. (https://doi.org/10.1096/fj.07-9492LSF)
Folmes CDL, Dzeja PP, Nelson TJ & & Terzic A 2012 Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11 596–606. (https://doi.org/10.1016/j.stem.2012.10.002)
Fu Y, Jia FB, Wang J, Song M, Liu SM, Li YF, Liu SZ & & Bu QW 2014 Effects of sub-chronic aluminum chloride exposure on rat ovaries. Life Sciences 100 61–66. (https://doi.org/10.1016/j.lfs.2014.01.081)
Garcia DN, Saccon TD, Pradiee J, Rincón JAA, Andrade KRS, Rovani MT, Mondadori RG, Cruz LAX, Barros CC, Masternak MM, et al.2019 Effect of caloric restriction and rapamycin on ovarian aging in mice. GeroScience 41 395–408. (https://doi.org/10.1007/s11357-019-00087-x)
Gibson GE, Chen H-L, Xu H, Qiu L, Xu Z, Denton TT & & Shi Q 2012 Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer’s disease-like calcium dysregulation. Neurobiology of Aging 33 1121.e13–1121.e24. (https://doi.org/10.1016/j.neurobiolaging.2011.11.003)
Gonzalo S 2010 Epigenetic alterations in aging. Journal of Applied Physiology 109 586–597. (https://doi.org/10.1152/japplphysiol.00238.2010)
Goud AP, Goud PT, Diamond MP, Gonik B & & Abu-Soud HM 2008 Reactive oxygen species and oocyte aging: role of superoxide, hydrogen peroxide, and hypochlorous acid. Free Radical Biology and Medicine 44 1295–1304. (https://doi.org/10.1016/j.freeradbiomed.2007.11.014)
Guimarães RM, Ribeiro LM, Sasaki LP, Nakagawa HM & & Cabral IO 2021 Oocyte morphology and reproductive outcomes - case report and literature review. JBRA Assisted Reproduction 25 500–507. (https://doi.org/10.5935/1518-0557.20210001)
Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, Maier AB & & Kennedy BK 2022 Alpha-ketoglutarate dietary supplementation to improve health in humans. Trends in Endocrinology and Metabolism 33 136–146. (https://doi.org/10.1016/j.tem.2021.11.003)
Hackett JA & & Surani MA 2014 Regulatory principles of pluripotency: from the ground state up. Cell Stem Cell 15 416–430. (https://doi.org/10.1016/j.stem.2014.09.015)
Hao Y, Wang J, Ren J, Liu Z, Bai Z, Liu G & & Dai Y 2022 Effect of dimethyl alpha-ketoglutarate supplementation on the in vitro developmental competences of ovine oocytes. Theriogenology 184 171–184. (https://doi.org/10.1016/j.theriogenology.2022.03.013)
Hardie DG, Ross FA & & Hawley SA 2012 AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Reviews. Molecular Cell Biology 13 251–262. (https://doi.org/10.1038/nrm3311)
Harris ID, Fronczak C, Roth L & & Meacham RB 2011 Fertility and the aging male. Reviews in Urology 13 e184–e190.
Harrison AP & & Pierzynowski SG 2008 BBiological effects of 2-oxoglutarate with particular emphasis on the regulation of protein, mineral and lipid absorption/metabolism, muscle performance, kidney function, bone formation and cancerogenesis, all viewed from a healthy ageing perspective state of the art--review article. Journal of Physiology and Pharmacology 59(Supplement 1) 91–106.
Hayashi Y, Otsuka K, Ebina M, Igarashi K, Takehara A, Matsumoto M, Kanai A, Igarashi K, Soga T & & Matsui Y 2017 Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells. PNAS 114 8289–8294. (https://doi.org/10.1073/pnas.1620915114)
He L, Xu Z, Yao K, Wu G, Yin Y, Nyachoti CM & & Kim SW 2015 The physiological basis and nutritional function of alpha-ketoglutarate. Current Protein and Peptide Science 16 576–581. (https://doi.org/10.2174/1389203716666150630140157)
Hoffmann I, Roatsch M, Schmitt ML, Carlino L, Pippel M, Sippl W & & Jung M 2012 The role of histone demethylases in cancer therapy. Molecular Oncology 6 683–703. (https://doi.org/10.1016/j.molonc.2012.07.004)
Hon GC, Song C-X, Du T, Jin F, Selvaraj S, Lee AY, Yen C-A, Ye Z, Mao S-Q, Wang B-A, et al.2014 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Molecular Cell 56 286–297. (https://doi.org/10.1016/j.molcel.2014.08.026)
Hou Y, Wang L, Ding B, Liu Y, Zhu H, Liu J, Li Y, Wu X, Yin Y & & Wu G 2010 Dietary alpha-ketoglutarate supplementation ameliorates intestinal injury in lipopolysaccharide-challenged piglets. Amino Acids 39 555–564. (https://doi.org/10.1007/s00726-010-0473-y)
Huang X, Liu J, Withers BR, Samide AJ, Leggas M & & Dickson RC 2013 Reducing signs of aging and increasing lifespan by drug synergy. Aging Cell 12 652–660. (https://doi.org/10.1111/acel.12090)
Huang J, Xue M, Zhang J, Yu H, Gu Y, Du M, Ye W, Wan B, Jin M & & Zhang Y 2019 Protective role of GPR120 in the maintenance of pregnancy by promoting decidualization via regulation of glucose metabolism. EBiomedicine 39 540–551. (https://doi.org/10.1016/j.ebiom.2018.12.019)
Hwang I-Y, Kwak S, Lee S, Kim H, Lee SE, Kim J-H, Kim YA, Jeon YK, Chung DH, Jin X, et al.2016 Psat1-dependent fluctuations in α-ketoglutarate affect the timing of ESC differentiation. Cell Metabolism 24 494–501. (https://doi.org/10.1016/j.cmet.2016.06.014)
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC & & Zhang Y 2010 Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466 1129–1133. (https://doi.org/10.1038/nature09303)
Jhanwar-Uniyal M, Wainwright JV, Mohan AL, Tobias ME, Murali R, Gandhi CD & & Schmidt MH 2019 Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship. Advances in Biological Regulation 72 51–62. (https://doi.org/10.1016/j.jbior.2019.03.003)
Jia Z, Feng Z, Wang L, Li H, Wang H, Xu D, Zhao X, Feng D & & Feng X 2018 Resveratrol reverses the adverse effects of a diet-induced obese murine model on oocyte quality and zona pellucida softening. Food and Function 9 2623–2633. (https://doi.org/10.1039/c8fo00149a)
Jiang Q, He L, Hou Y, Chen J, Duan Y, Deng D, Wu G, Yin Y & & Yao K 2016 Alpha-ketoglutarate enhances milk protein synthesis by porcine mammary epithelial cells. Amino Acids 48 2179–2188. (https://doi.org/10.1007/s00726-016-2249-5)
Jiang Q, Liu G, Wang X, Hou Y, Duan Y, Wu G, Yin Y & & Yao K 2017 Mitochondrial pathway is involved in the protective effects of alpha-ketoglutarate on hydrogen peroxide induced damage to intestinal cells. Oncotarget 8 74820–74835. (https://doi.org/10.18632/oncotarget.20426)
Jiang X, Xing X, Zhang Y, Zhang C, Wu Y, Chen Y, Meng R, Jia H, Cheng Y, Zhang Y, et al.2021 Lead exposure activates the Nrf2/Keap1 pathway, aggravates oxidative stress, and induces reproductive damage in female mice. Ecotoxicology and Environmental Safety 207 111231. (https://doi.org/10.1016/j.ecoenv.2020.111231)
Jin L, Chun J, Pan C, Kumar A, Zhang G, Ha Y, Li D, Alesi GN, Kang Y, Zhou L, et al.2018 The PLAG1-GDH1 axis promotes anoikis resistance and tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer. Molecular Cell 69 87–99.e7. (https://doi.org/10.1016/j.molcel.2017.11.025)
Kaelin WGJ & & McKnight SL 2013 Influence of metabolism on epigenetics and disease. Cell 153 56–69. (https://doi.org/10.1016/j.cell.2013.03.004)
Kapahi P, Zid BM, Harper T, Koslover D, Sapin V & & Benzer S 2004 Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Current Biology : CB 14 885–890. (https://doi.org/10.1016/j.cub.2004.03.059)
Klose RJ & & Zhang Y 2007 Regulation of histone methylation by demethylimination and demethylation. Nature Reviews. Molecular Cell Biology 8 307–318. (https://doi.org/10.1038/nrm2143)
Ko SY, Kang HY, Lee HS, Han SY & & Hong SH 2006 Identification of Jmjd1a as a STAT3 downstream gene in mES cells. Cell Structure and Function 31 53–62. (https://doi.org/10.1247/csf.31.53)
Kolaczkowski B & & Thornton JW 2004 Performance of maximum parsimony and likelihood phylogenetics when evolution is heterogeneous. Nature 431 980–984. (https://doi.org/10.1038/nature02917)
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, et al.2012 Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism 15 110–121. (https://doi.org/10.1016/j.cmet.2011.12.009)
Legendre F, MacLean A, Appanna VP & & Appanna VD 2020 Biochemical pathways to α-ketoglutarate, a multi-faceted metabolite. World Journal of Microbiology and Biotechnology 36 123. (https://doi.org/10.1007/s11274-020-02900-8)
Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A, et al.2013 Naive pluripotency is associated with global DNA hypomethylation. Nature Structural and Molecular Biology 20 311–316. (https://doi.org/10.1038/nsmb.2510)
Leon KE & & Aird KM 2019 Jumonji C demethylases in cellular senescence. Genes 10. (https://doi.org/10.3390/genes10010033)
Li Z & & Zhang H 2016 Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cellular and Molecular Life Sciences 73 377–392. (https://doi.org/10.1007/s00018-015-2070-4)
Li S-F, Liu H-X, Zhang Y-B, Yan Y-C & & Li Y-P 2010 The protective effects of alpha-ketoacids against oxidative stress on rat spermatozoa in vitro. Asian Journal of Andrology 12 247–256. (https://doi.org/10.1038/aja.2009.78)
Li T, Liu J, Liu K, Wang Q, Cao J, Xiao P, Yang W, Li X, Li J, Li M, et al.2023 Alpha-ketoglutarate ameliorates induced premature ovarian insufficiency in rats by inhibiting apoptosis and upregulating glycolysis. Reproductive Biomedicine Online 46 673–685. (https://doi.org/10.1016/j.rbmo.2023.01.005)
Liu S, He L & & Yao K 2018a The antioxidative function of alpha-ketoglutarate and its applications. BioMed Research International 2018 3408467. (https://doi.org/10.1155/2018/3408467)
Liu Z, Gan L, Zhang T, Ren Q & & Sun C 2018b Melatonin alleviates adipose inflammation through elevating α-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice. Journal of Pineal Research 64. (https://doi.org/10.1111/jpi.12455)
Liu H, Huang X, Mor G & & Liao A 2020 Epigenetic modifications working in the decidualization and endometrial receptivity. Cellular and Molecular Life Sciences 77 2091–2101. (https://doi.org/10.1007/s00018-019-03395-9)
Liu K, Wu Y, Yang W, Li T, Wang Z, Xiao S, Peng Z, Li M, Xiong W, Li M, et al.2024 α-Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3-Mediated pyroptosis of Granulosa Cells. Molecular Nutrition and Food Research 68 e2300784. (https://doi.org/10.1002/mnfr.202300784)
Loenarz C & & Schofield CJ 2011 Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends in Biochemical Sciences 36 7–18. (https://doi.org/10.1016/j.tibs.2010.07.002)
Loh Y-H, Zhang W, Chen X, George J & & Ng H-H 2007 Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes and Development 21 2545–2557. (https://doi.org/10.1101/gad.1588207)
Lord T & & Aitken RJ 2013 Oxidative stress and ageing of the post-ovulatory oocyte. Reproduction (Cambridge, England) 146 R217–R2 27. (https://doi.org/10.1530/REP-13-0111)
Lucenko MT, Andrievskaya IA & & Dolzhikova IV 2016 Energy metabolism in the placenta and the role of disturbances in the development of placental insufficiency at an exacerbation of Cytomegalovirus infection. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk 71 177–182. (https://doi.org/10.15690/vramn534)
Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, Bodmer R & & Oldham SM 2006 Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metabolism 4 133–142. (https://doi.org/10.1016/j.cmet.2006.05.013)
Lylyk MP, Bayliak MM, Shmihel HV, Storey JM, Storey KB & & Lushchak VI 2018 Effects of alpha-ketoglutarate on lifespan and functional aging of Drosophila melanogaster flies. Ukrainian Biochemical Journal 90 49–61. (https://doi.org/10.15407/ubj90.06.049)
Maekawa R, Tamura I, Shinagawa M, Mihara Y, Sato S, Okada M, Taketani T, Tamura H & & Sugino N 2019 Genome-wide DNA methylation analysis revealed stable DNA methylation status during decidualization in human endometrial stromal cells. BMC Genomics 20 324. (https://doi.org/10.1186/s12864-019-5695-0)
Mailloux RJ, Singh R, Brewer G, Auger C, Lemire J & & Appanna VD 2009 Alpha-ketoglutarate dehydrogenase and glutamate dehydrogenase work in tandem to modulate the antioxidant alpha-ketoglutarate during oxidative stress in Pseudomonas fluorescens. Journal of Bacteriology 191 3804–3810. (https://doi.org/10.1128/JB.00046-09)
Mariño G, Pietrocola F, Kong Y, Eisenberg T, Hill JA, Madeo F & & Kroemer G 2014 Dimethyl α-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy. Autophagy 10 930–932. (https://doi.org/10.4161/auto.28235)
Martínez-Reyes I & & Chandel NS 2020 Mitochondrial TCA cycle metabolites control physiology and disease. Nature Communications 11 102. (https://doi.org/10.1038/s41467-019-13668-3)
Maya S, Prakash T, Madhu KD & & Goli D 2016 Multifaceted effects of aluminium in neurodegenerative diseases: a review. Biomedicine and Pharmacotherapy = Biomedecine and Pharmacotherapie 83 746–754. (https://doi.org/10.1016/j.biopha.2016.07.035)
McDonough MA, Loenarz C, Chowdhury R, Clifton IJ & & Schofield CJ 2010 Structural studies on human 2-oxoglutarate dependent oxygenases. Current Opinion in Structural Biology 20 659–672. (https://doi.org/10.1016/j.sbi.2010.08.006)
Meng X, Liu H, Peng L, He W & & Li S 2022 Potential clinical applications of alpha‑ketoglutaric acid in diseases (Review). Molecular Medicine Reports 25. (https://doi.org/10.3892/mmr.2022.12667)
Miao Y-L, Kikuchi K, Sun Q-Y & & Schatten H 2009 Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility. Human Reproduction Update 15 573–585. (https://doi.org/10.1093/humupd/dmp014)
Miao Y, Cui Z, Gao Q, Rui R & & Xiong B 2020 Nicotinamide mononucleotide supplementation reverses the declining quality of maternally aged oocytes. Cell Reports 32 107987. (https://doi.org/10.1016/j.celrep.2020.107987)
Middaugh J, Hamel R, Jean-Baptiste G, Beriault R, Chenier D & & Appanna VD 2005 Aluminum triggers decreased aconitase activity via Fe-S cluster disruption and the overexpression of isocitrate dehydrogenase and isocitrate lyase: a metabolic network mediating cellular survival. Journal of Biological Chemistry 280 3159–3165. (https://doi.org/10.1074/jbc.M411979200)
Mikwar M, MacFarlane AJ & & Marchetti F 2020 Mechanisms of oocyte aneuploidy associated with advanced maternal age. Mutation Research. Reviews in Mutation Research 785 108320. (https://doi.org/10.1016/j.mrrev.2020.108320)
Min H, Lee M, Cho KS, Lim HJ & & Shim Y-H 2021 Nicotinamide supplementation improves oocyte quality and offspring development by modulating mitochondrial function in an aged Caenorhabditis elegans Model. Antioxidants 10 519. (https://doi.org/10.3390/antiox10040519)
Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A & & Aromataris E 2018 Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Medical Research Methodology 18 143. (https://doi.org/10.1186/s12874-018-0611-x)
Naeini SH, Mavaddatiyan L, Kalkhoran ZR, Taherkhani S & & Talkhabi M 2023 Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: evidences and perspectives. Experimental Gerontology 175 112154. (https://doi.org/10.1016/j.exger.2023.112154)
Niemiec T, Sikorska J, Harrison A, Szmidt M, Sawosz E, Wirth-Dzieciolowska E, Wilczak J & & Pierzynowski S 2011 Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice. Journal of Physiology and Pharmacology 62 37–43.
Orgad S, Nelson H, Segal D & & Nelson N 1998 Metal ions suppress the abnormal taste behavior of the Drosophila mutant malvolio. Journal of Experimental Biology 201 115–120. (https://doi.org/10.1242/jeb.201.1.115)
Pedroso AP, Dornellas APS, de Souza AP, Pagotto JF, Oyama LM, Nascimento CMO, Klawitter J, Christians U, Tashima AK & & Ribeiro EB 2019 A proteomics-metabolomics approach indicates changes in hypothalamic glutamate-GABA metabolism of adult female rats submitted to intrauterine growth restriction. European Journal of Nutrition 58 3059–3068. (https://doi.org/10.1007/s00394-018-1851-6)
Penn A, McPherson N, Fullston T, Arman B & & Zander-Fox D 2023 Maternal high-fat diet changes DNA methylation in the early embryo by disrupting the TCA cycle intermediary alpha ketoglutarate. Reproduction 165 347–362. (https://doi.org/10.1530/REP-22-0302)
Perrigue PM, Silva ME, Warden CD, Feng NL, Reid MA, Mota DJ, Joseph LP, Tian YI, Glackin CA, Gutova M, et al.2015 The histone demethylase jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines. Molecular Cancer Research 13 636–650. (https://doi.org/10.1158/1541-7786.MCR-13-0268)
Pfau R, Tzatsos A, Kampranis SC, Serebrennikova OB, Bear SE & & Tsichlis PN 2008 Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process. PNAS 105 1907–1912. (https://doi.org/10.1073/pnas.0711865105)
Polo JM, Anderssen E, Walsh RM, Schwarz BA, Nefzger CM, Lim SM, Borkent M, Apostolou E, Alaei S, Cloutier J, et al.2012 A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151 1617–1632. (https://doi.org/10.1016/j.cell.2012.11.039)
Qin D-Z, Cai H, He C, Yang D-H, Sun J, He W-L, Li B-L, Hua J-L & & Peng S 2021 Melatonin relieves heat-induced spermatocyte apoptosis in mouse testes by inhibition of ATF6 and PERK signaling pathways. Zoological Research 42 514–524. (https://doi.org/10.24272/j.issn.2095-8137.2021.041)
Radzki RP, Bienko M & & Pierzynowski SG 2012 Anti-osteopenic effect of alpha-ketoglutarate sodium salt in ovariectomized rats. Journal of Bone and Mineral Metabolism 30 651–659. (https://doi.org/10.1007/s00774-012-0377-x)
Radzki RP, Bienko M, Filip R & & Pierzynowski SG 2015 The protective and therapeutic effect of exclusive and combined treatment with alpha-ketoglutarate sodium salt and ipriflavone on bone loss in orchidectomized rats. Journal of Nutrition, Health and Aging 20 628–636. (https://doi.org/10.1007/s12603-015-0654-1)
Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, Bullinger L, Poschet G, Nonnenmacher Y, Barnert A, et al.2017 BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551 384–388. (https://doi.org/10.1038/nature24294)
Ren J, Hao Y, Liu Z, Li S, Wang C, Wang B, Liu Y, Liu G & & Dai Y 2021 Effect of exogenous glutathione supplementation on the in vitro developmental competence of ovine oocytes. Theriogenology 173 144–155. (https://doi.org/10.1016/j.theriogenology.2021.07.025)
Salminen A, Kaarniranta K, Hiltunen M & & Kauppinen A 2014a Krebs cycle dysfunction shapes epigenetic landscape of chromatin: novel insights into mitochondrial regulation of aging process. Cellular Signalling 26 1598–1603. (https://doi.org/10.1016/j.cellsig.2014.03.030)
Salminen A, Kauppinen A, Hiltunen M & & Kaarniranta K 2014b Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Ageing Research Reviews 16 45–65. (https://doi.org/10.1016/j.arr.2014.05.004)
Salminen A, Kauppinen A & & Kaarniranta K 2015 2-oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process. Cellular and Molecular Life Sciences 72 3897–3914. (https://doi.org/10.1007/s00018-015-1978-z)
Santonocito M, Guglielmino MR, Vento M, Ragusa M, Barbagallo D, Borzì P, Casciano I, Scollo P, Romani M, Tatone C, et al.2013 The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes. Apoptosis 18 201–211. (https://doi.org/10.1007/s10495-012-0783-5)
Sardina JL, Collombet S, Tian TV, Gómez A, Di Stefano B, Berenguer C, Brumbaugh J, Stadhouders R, Segura-Morales C, Gut M, et al.2018 Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell 23 727-741.e9. (https://doi.org/10.1016/j.stem.2018.08.016)
Sasaki H, Hamatani T, Kamijo S, Iwai M, Kobanawa M, Ogawa S, Miyado K & & Tanaka M 2019 Impact of oxidative stress on age-associated decline in oocyte developmental competence. Frontiers in Endocrinology 10 811. (https://doi.org/10.3389/fendo.2019.00811)
Satpute RM, Hariharakrishnan J & & Bhattacharya R 2010 Effect of alpha-ketoglutarate and N-acetyl cysteine on cyanide-induced oxidative stress mediated cell death in PC12 cells. Toxicology and Industrial Health 26 297–308. (https://doi.org/10.1177/0748233710365695)
Saxton RA & & Sabatini DM 2017 MTOR signaling in growth, metabolism, and disease. Cell 168 960–976. (https://doi.org/10.1016/j.cell.2017.02.004)
Sekita Y, Sugiura Y, Matsumoto A, Kawasaki Y, Akasaka K, Konno R, Shimizu M, Ito T, Sugiyama E, Yamazaki T, et al.2021 AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation. Stem Cell Research and Therapy 12 510. (https://doi.org/10.1186/s13287-021-02578-1)
Selman C, Tullet JMA, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, et al.2009 Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326 140–144. (https://doi.org/10.1126/science.1177221)
Shi Y & & Whetstine JR 2007 Dynamic regulation of histone lysine methylation by demethylases. Molecular Cell 25 1–14. (https://doi.org/10.1016/j.molcel.2006.12.010)
Shibata T, Bhat SA, Cao D, Saito S, Bernstein EA, Nishi E, Medenilla JD, Wang ET, Chan JL, Pisarska MD, et al.2024 Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ. Journal of Biological Chemistry 300 105486. (https://doi.org/10.1016/j.jbc.2023.105486)
Shrimali NM, Agarwal S, Kaur S, Bhattacharya S, Bhattacharyya S, Prchal JT & & Guchhait P 2021 α-Ketoglutarate inhibits thrombosis and inflammation by prolyl Hydroxylase-2 mediated inactivation of phospho-Akt. EBiomedicine 73 103672. (https://doi.org/10.1016/j.ebiom.2021.103672)
Sierra MI, Fernández AF & & Fraga MF 2015 Epigenetics of aging. Current Genomics 16 435–440. (https://doi.org/10.2174/1389202916666150817203459)
Song C, Peng W, Yin S, Zhao J, Fu B, Zhang J, Mao T, Wu H & & Zhang Y 2016 Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice. Scientific Reports 6 35165. (https://doi.org/10.1038/srep35165)
Su Y, Wang T, Wu N, Li D, Fan X, Xu Z, Mishra SK & & Yang M 2019 Alpha-ketoglutarate extends drosophila lifespan by inhibiting mTOR and activating AMPK. Aging 11 4183–4197. (https://doi.org/10.18632/aging.102045)
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, et al.2009 Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324 930–935. (https://doi.org/10.1126/science.1170116)
Tamura I, Fujimura T, Doi-Tanaka Y, Takagi H, Shirafuta Y, Kajimura T, Mihara Y, Maekawa R, Taketani T, Sato S, et al.2021 The essential glucose transporter GLUT1 is epigenetically upregulated by C/EBPβ and WT1 during decidualization of the endometrium. Journal of Biological Chemistry 297 101150. (https://doi.org/10.1016/j.jbc.2021.101150)
Tanaka K, Hayashi Y, Takehara A, Ito-Matsuoka Y, Tachibana M, Yaegashi N & & Matsui Y 2021 Abnormal early folliculogenesis due to impeded pyruvate metabolism in mouse oocytes. Biology of Reproduction 105 64–75. (https://doi.org/10.1093/biolre/ioab064)
Tang L, Xu X-H, Xu S, Liu Z, He Q, Li W, Sun J, Shuai W, Mao J, Zhao J-Y, et al.2023 Dysregulated Gln-Glu-α-ketoglutarate axis impairs maternal decidualization and increases the risk of recurrent spontaneous miscarriage. Cell Reports. Medicine 4 101026. (https://doi.org/10.1016/j.xcrm.2023.101026)
te Velde ER & & Pearson PL 2002 The variability of female reproductive ageing. Human Reproduction Update 8 141–154. (https://doi.org/10.1093/humupd/8.2.141)
Tennen RI, Bua DJ, Wright WE & & Chua KF 2011 SIRT6 is required for maintenance of telomere position effect in human cells. Nature Communications 2 433. (https://doi.org/10.1038/ncomms1443)
TeSlaa T, Chaikovsky AC, Lipchina I, Escobar SL, Hochedlinger K, Huang J, Graeber TG, Braas D & & Teitell MA 2016 α-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metabolism 24 485–493. (https://doi.org/10.1016/j.cmet.2016.07.002)
Tischler J, Gruhn WH, Reid J, Allgeyer E, Buettner F, Marr C, Theis F, Simons BD, Wernisch L & & Surani MA 2019 Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate. EMBO Journal 38 e99518. (https://doi.org/10.15252/embj.201899518)
Toivonen JM, Walker GA, Martinez-Diaz P, Bjedov I, Driege Y, Jacobs HT, Gems D & & Partridge L 2007 No influence of indy on lifespan in Drosophila after correction for genetic and cytoplasmic background effects. PLoS Genetics 3 e95. (https://doi.org/10.1371/journal.pgen.0030095)
Tran KA, Dillingham CM & & Sridharan R 2019 The role of α-ketoglutarate-dependent proteins in pluripotency acquisition and maintenance. Journal of Biological Chemistry 294 5408–5419. (https://doi.org/10.1074/jbc.TM118.000831)
Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, Moher D, Peters MDJ, Horsley T, Weeks L, et al.2018 PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Annals of Internal Medicine 169 467–473. (https://doi.org/10.7326/M18-0850)
Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, et al.2007 Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Molecular Cell 26 663–674. (https://doi.org/10.1016/j.molcel.2007.04.020)
Velvizhi S, Dakshayani KB & & Subramanian P 2002 Effects of alpha-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with ammonium acetate. Nutrition 18 747–750. (https://doi.org/10.1016/s0899-9007(0200825-0)
Wagner BM, Donnarumma F, Wintersteiger R, Windischhofer W & & Leis HJ 2010 Simultaneous quantitative determination of alpha-ketoglutaric acid and 5-hydroxymethylfurfural in human plasma by gas chromatography-mass spectrometry. Analytical and Bioanalytical Chemistry 396 2629–2637. (https://doi.org/10.1007/s00216-010-3479-0)
Walport LJ, Hopkinson RJ & & Schofield CJ 2012 Mechanisms of human histone and nucleic acid demethylases. Current Opinion in Chemical Biology 16 525–534. (https://doi.org/10.1016/j.cbpa.2012.09.015)
Wang L, Hou Y, Yi D, Li Y, Ding B, Zhu H, Liu J, Xiao H & & Wu G 2015 Dietary supplementation with glutamate precursor α-ketoglutarate attenuates lipopolysaccharide-induced liver injury in young pigs. Amino Acids 47 1309–1318. (https://doi.org/10.1007/s00726-015-1966-5)
Wang Y, Zang J, Zhang D, Sun Z, Qiu B & & Wang X 2018 KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth. OncoTargets and Therapy 11 201–209. (https://doi.org/10.2147/OTT.S149833)
Wang H, Xu J, Li H, Chen W, Zeng X, Sun Y & & Yang Q 2023 Alpha-ketoglutarate supplementation ameliorates ovarian reserve and oocyte quality decline with aging in mice. Molecular and Cellular Endocrinology 571 111935. (https://doi.org/10.1016/j.mce.2023.111935)
Ward PS & & Thompson CB 2012 Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21 297–308. (https://doi.org/10.1016/j.ccr.2012.02.014)
Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF, Lim R, Zimmermann B, Aspalter IM, Franco CA, Boettger T, et al.2016 FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529 216–220. (https://doi.org/10.1038/nature16498)
Willenborg M, Panten U & & Rustenbeck I 2009 Triggering and amplification of insulin secretion by dimethyl alpha-ketoglutarate, a membrane permeable alpha-ketoglutarate analogue. European Journal of Pharmacology 607 41–46. (https://doi.org/10.1016/j.ejphar.2009.02.014)
Wu Z, Du Y, Xue H, Wu Y & & Zhou B 2012 Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production. Neurobiology of Aging 33 199.e1–199.12. (https://doi.org/10.1016/j.neurobiolaging.2010.06.018)
Wu N, Yang M, Gaur U, Xu H, Yao Y & & Li D 2016 Alpha-ketoglutarate: physiological functions and applications. Biomolecules and Therapeutics 24 1–8. (https://doi.org/10.4062/biomolther.2015.078)
Wu X, Hu F, Zeng J, Han L, Qiu D, Wang H, Ge J, Ying X & & Wang Q 2019 NMNAT2-mediated NAD(+) generation is essential for quality control of aged oocytes. Aging Cell 18 e12955. (https://doi.org/10.1111/acel.12955)
Xiao D, Zeng L, Yao K, Kong X, Wu G & & Yin Y 2016 The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications. Amino Acids 48 2067–2080. (https://doi.org/10.1007/s00726-016-2254-8)
Xing M, Wang N, Zeng H & & Zhang J 2020 α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming. Journal of Biomedical Research 35 36–46. (https://doi.org/10.7555/JBR.34.20190160)
Xu Y & & Yang X 2022 Autophagy and pluripotency: self-eating your way to eternal youth. Trends in Cell Biology 32 868–882. (https://doi.org/10.1016/j.tcb.2022.04.001)
Xu Y, Zhang Y, García-Cañaveras JC, Guo L, Kan M, Yu S, Blair IA, Rabinowitz JD & & Yang X 2020 Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells. Science 369 397–403. (https://doi.org/10.1126/science.abb4467)
Xu C, Yuan Y, Zhang C, Zhou Y, Yang J, Yi H, Gyawali I, Lu J, Guo S, Ji Y, et al.2022 Smooth muscle AKG/OXGR1 signaling regulates epididymal fluid acid–base balance and sperm maturation. Life Metabolism 1 67–80. (https://doi.org/10.1093/lifemeta/loac012)
Yamada-Fukunaga T, Yamada M, Hamatani T, Chikazawa N, Ogawa S, Akutsu H, Miura T, Miyado K, Tarín JJ, Kuji N, et al.2013 Age-associated telomere shortening in mouse oocytes. Reproductive Biology and Endocrinology: RB&E 11 108. (https://doi.org/10.1186/1477-7827-11-108)
Yang Q, Cong L, Wang Y, Luo X, Li H, Wang H, Zhu J, Dai S, Jin H, Yao G, et al.2020 Increasing ovarian NAD+ levels improve mitochondrial functions and reverse ovarian aging. Free Radical Biology and Medicine 156 1–10. (https://doi.org/10.1016/j.freeradbiomed.2020.05.003)
Yang S-L, Tan H-X, Lai Z-Z, Peng H-Y, Yang H-L, Fu Q, Wang H-Y, Li D-J & & Li M-Q 2022 An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation. Cellular and Molecular Life Sciences 79 611. (https://doi.org/10.1007/s00018-022-04639-x)
Yao K, Yin Y, Li X, Xi P, Wang J, Lei J, Hou Y & & Wu G 2012 Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells. Amino Acids 42 2491–2500. (https://doi.org/10.1007/s00726-011-1060-6)
Ying Q-L, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P & & Smith A 2008 The ground state of embryonic stem cell self-renewal. Nature 453 519–523. (https://doi.org/10.1038/nature06968)
Ying M, You D, Zhu X, Cai L, Zeng S & & Hu X 2021 Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions. Redox Biology 46 102065. (https://doi.org/10.1016/j.redox.2021.102065)
You Y & & Liang W 2023 SIRT1 and SIRT6: the role in aging-related diseases. Biochimica et Biophysica Acta. Molecular Basis of Disease 1869 166815. (https://doi.org/10.1016/j.bbadis.2023.166815)
Yu Y, Liang D, Tian Q, Chen X, Jiang B, Chou B-K, Hu P, Cheng L, Gao P, Li J, et al.2014 Stimulation of somatic cell reprogramming by ERas-Akt-FoxO1 signaling axis. Stem Cells 32 349–363. (https://doi.org/10.1002/stem.1447)
Zdzisińska B, Żurek A & & Kandefer-Szerszeń M 2017 Alpha-ketoglutarate as a molecule with pleiotropic activity: well-known and novel possibilities of therapeutic use. Archivum Immunologiae et Therapiae Experimentalis 65 21–36. (https://doi.org/10.1007/s00005-016-0406-x)
Zhang J, Ratanasirintrawoot S, Chandrasekaran S, Wu Z, Ficarro SB, Yu C, Ross CA, Cacchiarelli D, Xia Q, Seligson M, et al.2016 LIN28 regulates stem cell metabolism and conversion to primed pluripotency. Cell Stem Cell 19 66–80. (https://doi.org/10.1016/j.stem.2016.05.009)
Zhang Z, He C, Zhang L, Zhu T, Lv D, Li G, Song Y, Wang J, Wu H, Ji P, et al.2019a Alpha-ketoglutarate affects murine embryo development through metabolic and epigenetic modulations. Reproduction 158 123–133. (https://doi.org/10.1530/REP-19-0018)
Zhang M, ShiYang X, Zhang Y, Miao Y, Chen Y, Cui Z & & Xiong B 2019b Coenzyme Q10 ameliorates the quality of postovulatory aged oocytes by suppressing DNA damage and apoptosis. Free Radical Biology and Medicine 143 84–94. (https://doi.org/10.1016/j.freeradbiomed.2019.08.002)
Zhang Z, He C, Gao Y, Zhang L, Song Y, Zhu T, Zhu K, Lv D, Wang J, Tian X, et al.2021 α-ketoglutarate delays age-related fertility decline in mammals. Aging Cell 20 e13291. (https://doi.org/10.1111/acel.13291)
Zhou W, Choi M, Margineantu D, Margaretha L, Hesson J, Cavanaugh C, Blau CA, Horwitz MS, Hockenbery D, Ware C, et al.2012 HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO Journal 31 2103–2116. (https://doi.org/10.1038/emboj.2012.71)
Zhou C, Zhang X, Zhang Y, ShiYang X, Li Y, Shi X & & Xiong B 2019 Vitamin C protects carboplatin-exposed oocytes from meiotic failure. Molecular Human Reproduction