Glycolysis: A fork in the path of normal and pathological pregnancy

Gou, Rui; Zhang, Xiaohong

doi:10.1096/fj.202301230r

Cited by 10 publications

(4 citation statements)

References 208 publications

(494 reference statements)

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“…Mammals develop in a hypoxic environment in utero with hypoxia being a known molecular trigger for normal fetal development and glycolysis being the predominant energy source. Increased secretion of glycolytic proteins in response to stress may stem from retained fetal pathways that allow for normal development in the setting of hypoxia [24,25,26,27]. Despite glycolytic metabolism, an anti-inflammatory phenotype was observed in both HIF-1α expressing and HIF-1α deficient neonatal BMDMs with hypoxic stress or LPS stimulation, suggesting that glycolysis may not induce a pro-inflammatory phenotype in neonatal BMDMs as has previously been described in adult BMDMs [28,29].…”

Section: Discussionmentioning

confidence: 83%

HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults

Becker,

Filipp,

Lantz

et al. 2024

Preprint

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The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1alpha; (HIF-1alpha). In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1alpha dependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.

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Section: Discussionmentioning

confidence: 83%

HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults

Becker,

Filipp,

Lantz

et al. 2024

Preprint

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“…At this stage, embryos exist in a reductive metabolic state where lactate helps maintain low pH and high reduction potential, which facilitates zygotic genome activation and erasure of epigenetic modifications. After the morula stage, glucose utilization increases in embryos as they begin employing the tricarboxylic acid cycle and oxidative phosphorylation for ATP production [27]. Hence, lactate levels gradually decline while TCA cycle intermediates like α-ketoglutarate rise in embryos.…”

Section: Discussionmentioning

confidence: 99%

Histone Lactylation Is Involved in Mouse Oocyte Maturation and Embryo Development

Yang,

Zheng,

et al. 2024

IJMS

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Numerous post-translational modifications are involved in oocyte maturation and embryo development. Recently, lactylation has emerged as a novel epigenetic modification implicated in the regulation of diverse cellular processes. However, it remains unclear whether lactylation occurs during oocyte maturation and embryo development processes. Herein, the lysine lactylation (Kla) modifications were determined during mouse oocyte maturation and early embryo development by immunofluorescence staining. Exogenous lactate was supplemented to explore the consequences of modulating histone lactylation levels on oocyte maturation and embryo development processes by transcriptomics. Results demonstrated that lactylated proteins are widely present in mice with tissue- and cell-specific distribution. During mouse oocyte maturation, immunofluorescence for H3K9la, H3K14la, H4K8la, and H4K12la was most intense at the germinal vesicle (GV) stage and subsequently weakened or disappeared. Further, supplementing the culture medium with 10 mM sodium lactate elevated both the oocyte maturation rate and the histone Kla levels in GV oocytes, and there were substantial increases in Kla levels in metaphase II (MII) oocytes. It altered the transcription of molecules involved in oxidative phosphorylation. Moreover, histone lactylation levels changed dynamically during mouse early embryogenesis. Sodium lactate at 10 mM enhanced early embryo development and significantly increased lactylation, while impacting glycolytic gene transcription. This study reveals the roles of lactylation during oocyte maturation and embryo development, providing new insights to improving oocyte maturation and embryo quality.

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“…Extra villous trophoblasts, crucial for maternal-fetal blood circulation, exhibit heightened metabolic activity during this period, are heavily reliant on glycolysis, and are thus expected to result in increased MGO and AGE production. 41 As gestation progresses beyond the first trimester, trophoblast subtypes transition from proliferative cytotrophoblast (more glycolytically active) to nonproliferating syncytiotrophoblast cells (less glycolytically active), with extra villous trophoblasts adapting to their roles, potentially stabilizing biomarker levels as placental maturation occurs. 7 , 42 This is in line with our observations that the AGEs CML, CEL, and MG-H2 in the placenta are all 3 negatively correlated with gestational age.…”

Section: Discussionmentioning

confidence: 99%

Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications

Vangrieken,

Al-Nasiry,

Remels

et al. 2024

Hypertension

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BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (N ε -(carboxymethyl)lysine [CML], N ε -(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (−12%) and hypoxia-exposed placentas (−16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (−26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia.

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Glycolysis: A fork in the path of normal and pathological pregnancy

Cited by 10 publications

References 208 publications

HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults

HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults

Histone Lactylation Is Involved in Mouse Oocyte Maturation and Embryo Development

Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications

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