Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction

Adant, Isabelle; Bird, Matthew; Decru, Bram; Windmolders, Petra; Wallays, Marie; Witte, Peter de; Rymen, Daisy; Witters, Peter; Vermeersch, Pieter; Cassiman, David; Ghesquière, Bart

doi:10.1016/j.molmet.2022.101537

Cited by 13 publications

(11 citation statements)

References 48 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several lines of study have revealed that ferroptosis serves a pathogenic role in sepsis-induced ALI [ 40 , 41 , 42 ]. Uridine was extensively reported to exhibit antioxidant effect and regarded as an antioxidative metabolite [ 18 , 43 ]. For example, it has been covered that uridine converted to uridine diphosphate (UDP) and subsequently activated mitoKATP to suppress ROS production in myocardial tissue [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is conceivable theoretically that the elaborately regulated processes of uridine metabolism are inseparable from its essential role in modulating pathophysiological processes. As a matter of fact, emerging researches have reported that uridine exerts anti-inflammation [ 14 , 15 ], anti-fibrosis [ 16 ], antioxidation [ 17 , 18 , 19 ] and anti-aging functions [ 20 ]. For example, Irina B. Krylova1 discovered that uridine treatment attenuated myocardial ischemic-reperfusion injury via antioxidation by activating ATP-dependent potassium (mitoKATP) channel [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Lai

Song

Gao

et al. 2023

IJMS

View full text Add to dashboard Cite

Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Lai

Song

Gao

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Moreover, 1-acyl-sn-glycero-3-phosphocholines are also connected to sn-glycerol-3-phosphate (G3P), a metabolite which branches off from the main glycolytic pathway through the conversion of dihydroxyacetone phosphate (DHAP) by the enzyme G3P dehydrogenase and provides the backbone onto which the fatty acids are connected. In a previous study, it was also shown that mitochondrial related IEM showed higher use of the glycerol 3 phosphate shuttle 17 .…”

Section: Resultsmentioning

confidence: 83%

Integrating multiple omics levels using the human protein complexome as a framework, a multi-omics study of inborn errors of metabolism

Guharoy,

Adant,

Bird

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Proteins organize into functional assemblies that drive diverse biological activities. Leveraging a comprehensive dataset of manually curated annotations for the human protein complexome, we investigated biological perturbations at the protein complex level. Using proteomics and transcriptomics data from fibroblasts of patients with inborn errors of metabolism (IEM) and control samples, we globally mapped information onto complex subunits to discern affected processes. Across the patient cohort (consisting of organic acidaemias, fatty acid oxidation defects and mitochondrial respiratory chain defect IEMs), mitochondrial oxidative phosphorylation emerged as the most perturbed pathway, identified through proteomics datasets. Simultaneously, metabolomics highlighted significant regulation of phospholipids in patients with Fatty Acid and Mitochondrial IEM. Moreover, proteomics analysis also revealed the dysregulation of protein complexes involved in histone (de)acetylation, a finding validated through Western Blot analysis measuring histone acetylation levels. This introduces a novel epigenetic dimension to IEM and metabolic research, suggesting avenues for further exploration. Our study demonstrates a multiomics data integration concept that maps proteomics and transcriptomics data onto model organism complexomes. This integrative approach can be extended to metabolomics and lipidomics, associating information with complexes having metabolic functions, such as enzymatic complexes. This global strategy for identifying disease-relevant perturbations offers a systems-wide perspective on molecular-level physiological and pathological changes. Such insights are crucial for devising clinical intervention strategies and prioritizing druggable pathways and complexes. The presented methodology provides a foundation for future investigations, emphasizing the importance of integrating multiomics data to comprehensively understand cellular machinery alterations and facilitate targeted therapeutic approaches.

show abstract

“…The mitochondrial rate-limiting enzyme in pyrimidine synthesis, DHODH, uses coenzyme Q as electron acceptor and is therefore dependent on a functional respiratory chain ( 32 ). For this reason, respiratory deficient cells cannot grow without uridine supplementation ( 33, 34 ). Uridine is a precursor of RNA and phospholipids and can be converted in ribose-1-phosphate that enter glycolysis to fuel ATP production ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy

Zaninello,

Schlegel,

Nolte

et al. 2023

Preprint

View full text Add to dashboard Cite

Transport and local translation of mRNAs in distal axonal compartments are essential for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects mitochondria from damage during their long journey along the axon, however the regulatory factors involved are largely unknown. Here, we show that CLUH, a cytosolic protein that binds mRNAs encoding mitochondrial proteins, is essential for preventing axonal degeneration of spinal motoneurons and maintaining motor behavior in the mouse. We demonstrate that CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The absence of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits specifically in the growth cone. CLUH binds ribosomal subunits, translation initiation and ribosome recycling components, and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the growth cone and translation defects in CLUH-deficient motoneurons. In conclusion, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which are essential for their development and long-term integrity and function.

show abstract

Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction

Cited by 13 publications

References 48 publications

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Integrating multiple omics levels using the human protein complexome as a framework, a multi-omics study of inborn errors of metabolism

CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy

Contact Info

Product

Resources

About