Dataset Information

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome.

ABSTRACT:

Background

Sepsis-induced cardiomyopathy (SIC) is a major contributing factor for morbidity and mortality in sepsis. Accumulative evidence has suggested that cardiac mitochondrial oxidative phosphorylation is attenuated in sepsis, but the underlying molecular mechanisms remain incompletely understood.

Methods

Adult male mice of 9 to 12 weeks old were subjected to sham or cecal ligation and puncture procedure. Echocardiography in vivo and Langendorff-perfused hearts were used to assess cardiac function 24 h after the procedures. Unbiased proteomics analysis was performed to profile mitochondrial proteins in the hearts of both sham and SIC mice. Seahorse respirator technology was used to evaluate oxygen consumption in purified mitochondria.

Results

Of the 665 mitochondrial proteins identified in the proteomics assay, 35 were altered in septic mice. The mitochondrial remodeling involved various energy metabolism pathways including subunits of the electron transport chain, fatty acid catabolism, and carbohydrate oxidative metabolism. We also identified a significant increase of pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and inhibition of PDH activity in septic hearts. Furthermore, compared to sham mice, mitochondrial oxygen consumption of septic mice was significantly reduced when pyruvate was provided as a substrate. However, it was unchanged when PDH was bypassed by directly supplying the Complex I substrate NADH, or by using the Complex II substrate succinate, or using Complex IV substrate, or by providing the beta-oxidation substrate palmitoylcarnitine, neither of which require PDH for mitochondrial oxygen consumption.

Conclusions

These data demonstrate a broad mitochondrial protein remodeling, PDH inactivation and impaired pyruvate-fueled oxidative phosphorylation during SIC, and provide a molecular framework for further exploration.

SUBMITTER: Shimada BK

PROVIDER: S-EPMC8904652 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome.

Shimada Briana K BK Boyman Liron L Huang Weiliang W Zhu Jing J Yang Yang Y Chen Fengqian F Kane Maureen A MA Yadava Nagendra N Zou Lin L Lederer W Jonathan WJ Polster Brian M BM Chao Wei W

Shock (Augusta, Ga.) 20220401 4

<h4>Background</h4>Sepsis-induced cardiomyopathy (SIC) is a major contributing factor for morbidity and mortality in sepsis. Accumulative evidence has suggested that cardiac mitochondrial oxidative phosphorylation is attenuated in sepsis, but the underlying molecular mechanisms remain incompletely understood.<h4>Methods</h4>Adult male mice of 9 to 12 weeks old were subjected to sham or cecal ligation and puncture procedure. Echocardiography in vivo and Langendorff-perfused hearts were used to as ...[more]

PMID: 34506367

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Project description:Introduction: Sepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSC suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism has been demonstrated to shape cell responses and regulate immune suppression or enhance effector activity. While the metabolism of MDSC has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in MDSC during and after sepsis and stratify these patients by characteristics and outcome to determine differences that may guide treatment decisions. Methods: Peripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at four days, 2-3 weeks, and 6 months underwent CD66b+ or CD3+ isolation, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and epigenetic analysis. Results: Mitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC) were decreased in MDSC from septic patients at four days after infection and persisted for up to six months after sepsis onset. Glycolysis was not impacted by sepsis. In contrast, oxidative metabolism in CD3+ T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSC in septic patients was also linked to significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b+ cells isolated from PBMC healthy participants and patients with sepsis at four days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and two long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3, NR4A2, and TAMLIN/NR4A1 (all critical for mitochondrial biogenesis) expression were persistently decreased with reduced chromatin accessibility indicative of gene silencing. Discussion: After sepsis, PBMC CD66b+ cells present with a unique metabolic signature that is not shared with CD3+ T-cell subsets in these patients or other disease cohorts. These changes in mitochondrial function result from a reduced content of these organelles. We have identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight a need to target metabolism in sepsis to promote immune homeostasis and recovery.

Dataset Information

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome.

Background

Methods

Results

Conclusions

Publications

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome.

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