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OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration

ABSTRACT: OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration

PROVIDER: PRJNA983839 | ENA |

REPOSITORIES: ENA

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OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [Astyanax_mexicanus_RNAseq]

Project description:In contrast to humans after myocardial infarction, fish can fully regenerate their hearts. However, not all fish are equally able to regenerate, allowing comparative inter- and intra-species analysis to identify novel mechanisms controlling successful heart regeneration. Here, we report a differential regenerative response to cardiac cryo-injury between seven different wild-type zebrafish strains. Correlating this data to single cell and bulk RNAseq data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by Glycolysis through the Malate aspartate shuttle (MAS), increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. We confirm these findings in Astyanax mexicanus and link it to a dynamic temporal sarcomere gene expression programme during cardiomyocyte re-differentiation. These findings challenge the current stance that OXPHOS inhibits regeneration and provide new targetable pathways to enhance heart repair in humans after myocardial infarction.

2025-07-31 | GSE234989 | GEO

OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [WT_ZF_strain_RNAseq]

2025-07-31 | GSE234934 | GEO

OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [scRNA-seq]

2025-07-31 | GSE237276 | GEO

OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [WT_ZF_strain_RNAseq]

Project description:OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [WT_ZF_strain_RNAseq]

| PRJNA983773 | ENA

OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [Astyanax_mexicanus_RNAseq]

Project description:OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [Astyanax_mexicanus_RNAseq]

| PRJNA983844 | ENA

OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [scRNA-seq]

Project description:OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [scRNA-seq]

| PRJNA994513 | ENA

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

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

| PRJNA1272488 | ENA

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

Project description: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.

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The Malate Shuttle Detoxifies Ammonia in Exhausted T Cells by Producing 2-Ketoglutarate

Project description:The malate shuttle is traditionally known to maintain the NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions was unknown. Here we show that chronic viral infections induced the expression of GOT1, the key enzyme in the malate shuttle, in CD8+ T cells. Got1 deficiency indeed decreased the NAD+/NADH ratio and dampened antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore antiviral T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate and led to toxic ammonia accumulation in CD8+ T cells. Supplementation with 2-ketoglutarate assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. This study suggests that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH ratio, but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infections.

2023-09-01 | GSE220876 | GEO

OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-07-31 | GSE234990 | GEO