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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: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Astyanax mexicanus Danio rerio

PROVIDER: GSE234990 | GEO | 2025/07/31

REPOSITORIES: GEO

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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

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

| PRJNA983839 | ENA

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

C/EBPβ-LIP mediated activation of the malate-aspartate shuttle sensitizes cells to glycolysis inhibition.

Project description:ObjectiveCancer cells use glycolysis for generation of metabolic intermediates and ATP needed for cell growth and proliferation. The transcription factor C/EBPβ-LIP stimulates glycolysis and mitochondrial respiration in cancer cells. We initially observed that high expression of C/EBPβ-LIP makes cells vulnerable to treatment with the glycolysis inhibitor 2-deoxyglucose. The aim of the study was to uncover the involved mechanisms of C/EBPβ-LIP induced sensitivity to glycolysis inhibition.MethodsWe used genetically engineered cell lines to examine the effect of C/EBPβ-LIP and -LAP protein isoforms on glycolysis and NADH/NAD+ metabolism in mouse embryonic fibroblasts (MEFs), and triple negative breast cancer (TNBC) cells that endogenously express high levels of C/EBPβ-LIP. Analyses included assays of cell proliferation, cell survival and metabolic flux (OCR and ECAR by Seahorse XF96). Small molecule inhibitors were used to identify underlying metabolic pathways that mediate sensitivity to glycolysis inhibition induced by C/EBPβ-LIP.ResultsThe transcription factor C/EBPβ-LIP stimulates both glycolysis and the malate-aspartate shuttle (MAS) and increases the sensitivity to glycolysis inhibition (2-deoxyglucose) in fibroblasts and breast cancer cells. Inhibition of glycolysis with ongoing C/EBPβ-LIP-induced MAS activity results in NADH depletion and apoptosis that can be rescued by inhibiting either the MAS or other NAD+-regenerating processes.ConclusionThis study indicates that a low NADH/NAD+ ratio is an essential mediator of 2-deoxyglucose toxicity in cells with high cytoplasmic NAD+-regeneration capacity and that simultaneous inhibition of glycolysis and lowering of the NADH/NAD+ ratio may be considered to treat cancer.

| S-EPMC10160650 | biostudies-literature

Inborn disorders of the malate aspartate shuttle.

Project description:Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD+ /NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox-dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3-phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation.

| S-EPMC8362162 | biostudies-literature

Deficiency of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis.

Project description:BackgroundAspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of intracellular aspartate levels on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD+/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.ResultsLow AGC1 expression correlates with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells.ConclusionThis study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation, do not always reflect metastatic capacity in vivo.

| S-EPMC7690131 | biostudies-literature

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