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Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction.
Adant, Isabelle; Bird, Matthew; Decru, Bram; Windmolders, Petra; Wallays, Marie; de Witte, Peter; Rymen, Daisy; Witters, Peter; Vermeersch, Pieter; Cassiman, David; Ghesquière, Bart.
Afiliación
  • Adant I; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium; Metabolomics Expertise Center, Center for Cancer Biology, CCB-VIB, VIB, Leuven, 3000, Belgium.
  • Bird M; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium; Metabolomics Expertise Center, Center for Cancer Biology, CCB-VIB, VIB, Leuven, 3000, Belgium; Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, 3000, Bel
  • Decru B; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium; Metabolomics Expertise Center, Center for Cancer Biology, CCB-VIB, VIB, Leuven, 3000, Belgium.
  • Windmolders P; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium.
  • Wallays M; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium.
  • de Witte P; Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.
  • Rymen D; Metabolic Centre, University Hospitals Leuven, Leuven, 3000, Belgium.
  • Witters P; Metabolic Centre, University Hospitals Leuven, Leuven, 3000, Belgium.
  • Vermeersch P; Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, 3000, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, 3000, Belgium.
  • Cassiman D; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium; Metabolic Centre, University Hospitals Leuven, Leuven, 3000, Belgium. Electronic address: david.cassiman@kuleuven.be.
  • Ghesquière B; Metabolomics Expertise Center, Center for Cancer Biology, CCB-VIB, VIB, Leuven, 3000, Belgium; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, 3000, Belgium. Electronic address: bart.ghesquiere@kuleuven.be.
Mol Metab ; 63: 101537, 2022 09.
Article en En | MEDLINE | ID: mdl-35772644
INTRODUCTION: Primary mitochondrial diseases (PMD) are a large, heterogeneous group of genetic disorders affecting mitochondrial function, mostly by disrupting the oxidative phosphorylation (OXPHOS) system. Understanding the cellular metabolic re-wiring occurring in PMD is crucial for the development of novel diagnostic tools and treatments, as PMD are often complex to diagnose and most of them currently have no effective therapy. OBJECTIVES: To characterize the cellular metabolic consequences of OXPHOS dysfunction and based on the metabolic signature, to design new diagnostic and therapeutic strategies. METHODS: In vitro assays were performed in skin-derived fibroblasts obtained from patients with diverse PMD and validated in pharmacological models of OXPHOS dysfunction. Proliferation was assessed using the Incucyte technology. Steady-state glucose and glutamine tracing studies were performed with LC-MS quantification of cellular metabolites. The therapeutic potential of nutritional supplements was evaluated by assessing their effect on proliferation and on the metabolomics profile. Successful therapies were then tested in a in vivo lethal rotenone model in zebrafish. RESULTS: OXPHOS dysfunction has a unique metabolic signature linked to an NAD+/NADH imbalance including depletion of TCA intermediates and aspartate, and increased levels of glycerol-3-phosphate. Supplementation with pyruvate and uridine fully rescues this altered metabolic profile and the subsequent proliferation deficit. Additionally, in zebrafish, the same nutritional treatment increases the survival after rotenone exposure. CONCLUSIONS: Our findings reinforce the importance of the NAD+/NADH imbalance following OXPHOS dysfunction in PMD and open the door to new diagnostic and therapeutic tools for PMD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Enfermedades Mitocondriales Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Mol Metab Año: 2022 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Enfermedades Mitocondriales Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Mol Metab Año: 2022 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Alemania