Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction
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 developmen...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001065 |
| _version_ | 1798037718708518912 |
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| author | Isabelle Adant Matthew Bird Bram Decru Petra Windmolders Marie Wallays Peter de Witte Daisy Rymen Peter Witters Pieter Vermeersch David Cassiman Bart Ghesquière |
| author_facet | Isabelle Adant Matthew Bird Bram Decru Petra Windmolders Marie Wallays Peter de Witte Daisy Rymen Peter Witters Pieter Vermeersch David Cassiman Bart Ghesquière |
| author_sort | Isabelle Adant |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T21:30:22Z |
| format | Article |
| id | doaj.art-7ed8e9ba5937483b8ad271db0b82cab8 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-11T21:30:22Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-7ed8e9ba5937483b8ad271db0b82cab82022-12-22T04:02:01ZengElsevierMolecular Metabolism2212-87782022-09-0163101537Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunctionIsabelle Adant0Matthew Bird1Bram Decru2Petra Windmolders3Marie Wallays4Peter de Witte5Daisy Rymen6Peter Witters7Pieter Vermeersch8David Cassiman9Bart Ghesquière10Laboratory 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, BelgiumLaboratory 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, BelgiumLaboratory 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, BelgiumLaboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, BelgiumLaboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, BelgiumMetabolic Centre, University Hospitals Leuven, Leuven, 3000, BelgiumMetabolic Centre, University Hospitals Leuven, Leuven, 3000, BelgiumClinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, 3000, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, 3000, BelgiumLaboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium; Metabolic Centre, University Hospitals Leuven, Leuven, 3000, Belgium; Corresponding author. 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; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, 3000, Belgium; Corresponding author. Metabolomics Expertise Center, Center for Cancer Biology, CCB-VIB, VIB, Leuven, 3000, Belgium.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.http://www.sciencedirect.com/science/article/pii/S2212877822001065Primary mitochondrial diseaseOXPHOSAspartic acidTreatmentPyruvate and uridine |
| spellingShingle | Isabelle Adant Matthew Bird Bram Decru Petra Windmolders Marie Wallays Peter de Witte Daisy Rymen Peter Witters Pieter Vermeersch David Cassiman Bart Ghesquière Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction Molecular Metabolism Primary mitochondrial disease OXPHOS Aspartic acid Treatment Pyruvate and uridine |
| title | Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction |
| title_full | Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction |
| title_fullStr | Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction |
| title_full_unstemmed | Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction |
| title_short | Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction |
| title_sort | pyruvate and uridine rescue the metabolic profile of oxphos dysfunction |
| topic | Primary mitochondrial disease OXPHOS Aspartic acid Treatment Pyruvate and uridine |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001065 |
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