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

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

PROVIDER: PRJNA911793 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22715500_1.fastq.gz	Fastqsanger.gz
	SRR22715500_2.fastq.gz	Fastqsanger.gz
	SRR22715501_1.fastq.gz	Fastqsanger.gz
	SRR22715501_2.fastq.gz	Fastqsanger.gz
	SRR22715502_1.fastq.gz	Fastqsanger.gz

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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

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

Project description:The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

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A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS

Project description:Tumor necrosis factor (TNF) causes a lethal systemic inflammatory response syndrome (SIRS) which is characterized by significant metabolic alterations. Based on liver RNA sequencing, we found that TNF impairs the malate-aspartate shuttle (MAS), an essential redox shuttle that transfers reducing equivalents across the inner mitochondrial membrane thereby recycling cytosolic NAD+. This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4α function, which appears to be the key transcription factor involved. Using Slc25a13-/- mice lacking citrin – a crucial MAS component – we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD+ regeneration leads to diminished mitochondrial β-oxidation, leading to elevated levels of circulating free fatty acids (FFAs) and to hepatic lipid accumulation. Simultaneously, MAS dysfunction promotes glycolysis coupled to lactate production and reduces lactate-mediated gluconeogenesis, culminating in severe hyperlactatemia that triggers VEGF-induced vascular leakage. Overall, MAS dysfunction contributes to metabolic failure and lethality in TNF-induced SIRS, highlighting its potential as a promising, therapeutic target.

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

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Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2 (MDH2)

Project description:Glioblastoma (GBM) ranks among the most lethal of human cancers with current therapies offering only palliation. GBM displays striking intratumoral heterogeneity with diversity of cell state, metabolism, and molecular regulation. Here, we demonstrate that stem-like tumor cells, designated GBM stem cells (GSCs), display higher activity of the malate aspartate shuttle (MAS) through increased expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 reduced GSC proliferation, self-renewal, and in vivo tumor growth. MDH2 targeting induced accumulation of alpha-ketoglutarate (αKG), a critical enzymatic co-factor. Mechanistically, MDH2 regulated post-transcriptional regulation of mRNA, specifically N6-Methyladenosine (m6A) with platelet-derived growth factor receptor- (PDGFR) as a regulated transcript. Leveraging these observations, targeting MDH2 and PDGFR displayed combinatorial efficacy against GSCs. Collectively, these results suggest that stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes that reveal possible therapeutic paradigms.

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2025-06-12 | GSE299062 | GEO

A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS

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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.

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