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Lactate deficiency-induced early embryonic arrest is mitigated through malate-aspartate shuttle

ABSTRACT: During assisted reproductive technology (ART) procedure, approximately one third to half of the in vitro fertilization (IVF) derived embryos cannot reach the blastocyst stage, and about 10% arrest at the early cleavage stage. Early mammalian embryos obtain nutrients from maternal environment to fulfill the energy requirements of growth and development, and lactate is one of the major substrates of embryo energy metabolism. To explicitly reveal the energy metabolism in early embryogenesis, we inhibited the production and uptake of lactate at the zygote stage, and found it resulted developmental arrest, impaired mitochondrial activity and reduced NAD+/NADH ratio. By activating the malate-aspartate shuttle (MAS), the developmental arrest was rescued through the restoration of NAD+/NADH balance. Therefore, we demonstrate that maternal LDHB plays an essential role from 4- to 8-cell stage that it converts lactate from pyruvate to generate NAD+, and MAS activation is responsible for the re-equilibrium of NAD+/NADH. Our study discusses the association of metabolic flexibility and developmental regulation, and deepens our understanding of the metabolic mechanism of embryonic development.

ORGANISM(S): Mus musculus

PROVIDER: GSE299062 | GEO | 2025/06/12

REPOSITORIES: GEO

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Project description:Previous findings have demonstrated that the NADH/NAD+ ratio has a strong impact on the glycolytic flux in C. glutamicum under anaerobic conditions in the absence of external electron acceptors. During an attempt to rewire anaerobic metabolism to achieve high yield formation of ethanol, we inactivated the malate dehydrogenase and lactate dehydrogenase in a C. glutamicum strain expressing pyruvate decarboxylase and alcohol dehydrogenase, to eliminate formation of the by-products succinate and lactate, respectively. This modification increased the yield of ethanol but had a negative effect on glycolysis, which we found to correlate with an elevated NADH/NAD+ ratio. The pyruvate dehydrogenase (PDH) of C. glutamicum is active under anaerobic conditions, and can potentially exacerbate the negative effect on glycolysis, due to NADH formation. To reduce PDH activity under anaerobic conditions, we decided to replace the gene encoding the E3 subunit of PDH with its Escherichia coli counterpart, as E. coli PDH has been reported to be functional under aerobic conditions only. The resultant strain JS133 produced far less acetate with a further increased ethanol production, however, the glycolytic flux was still low. After observing differences in glycolytic flux for JS133 on glucose and fructose, we speculated that the pentose phosphate pathway (PPP) might be involved in the reduced flux on glucose. To prove this, we deleted the zwf gene, encoding glucose-6-phosphate dehydrogenase, which is the entry point into PPP, and immediately observed a stimulating effect on glycolysis. Subsequent characterization revealed a direct correlation between the intracellular NADH/NAD+ and NADPH/NADP+ ratios under anoxic conditions. Based on these findings we managed to re-channel the metabolism of C. glutamicum successfully towards either to ethanol or D-lactate with 92% and 98% of the theoretical yield respectively, which is the highest yields for D-lactate production thus far reported in the literature.

Project description:Aubert2005 - Interaction between astrocytes and neurons on energy metabolism Enocded non-curated model. Issues: - Confusing equations A.41 and A.42 - Missing values for parameters Vv,0 and dHb,0 This model is described in the article: Interaction between astrocytes and neurons studied using a mathematical model of compartmentalized energy metabolism. Aubert A, Costalat R. J. Cereb. Blood Flow Metab. 2005 Nov; 25(11): 1476-1490 Abstract: Understanding cerebral energy metabolism in neurons and astrocytes is necessary for the interpretation of functional brain imaging data. It has been suggested that astrocytes can provide lactate as an energy fuel to neurons, a process referred to as astrocyte-neuron lactate shuttle (ANLS). Some authors challenged this hypothesis, defending the classical view that glucose is the major energy substrate of neurons, at rest as well as in response to a stimulation. To test the ANLS hypothesis from a theoretical point of view, we developed a mathematical model of compartmentalized energy metabolism between neurons and astrocytes, adopting hypotheses highly unfavorable to ANLS. Simulation results can be divided between two groups, depending on the relative neuron versus astrocyte stimulation. If this ratio is low, ANLS is observed during all the stimulus and poststimulus periods (continuous ANLS), but a high ratio induces ANLS only at the beginning of the stimulus and during the poststimulus period (triphasic behavior). Finally, our results show that current experimental data on lactate kinetics are compatible with the ANLS hypothesis, and that it is essential to assess the neuronal and astrocytic NADH/NAD+ ratio changes to test the ANLS hypothesis. This model is hosted on BioModels Database and identified by: MODEL1411210000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Lactate deficiency-induced early embryonic arrest is mitigated through malate-aspartate shuttle

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