Metabolic effects of bezafibrate in mitochondrial disease
Abstract Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open‐label observational experimental medicine study of six patients with...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911589 |
| _version_ | 1827015192778637312 |
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| author | Hannah Steele Aurora Gomez‐Duran Angela Pyle Sila Hopton Jane Newman Renae J Stefanetti Sarah J Charman Jehill D Parikh Langping He Carlo Viscomi Djordje G Jakovljevic Kieren G Hollingsworth Alan J Robinson Robert W Taylor Leonardo Bottolo Rita Horvath Patrick F Chinnery |
| author_facet | Hannah Steele Aurora Gomez‐Duran Angela Pyle Sila Hopton Jane Newman Renae J Stefanetti Sarah J Charman Jehill D Parikh Langping He Carlo Viscomi Djordje G Jakovljevic Kieren G Hollingsworth Alan J Robinson Robert W Taylor Leonardo Bottolo Rita Horvath Patrick F Chinnery |
| author_sort | Hannah Steele |
| collection | DOAJ |
| description | Abstract Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open‐label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600–1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV‐immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF‐21), growth and differentiation factor 15 (GDF‐15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long‐term sequelae. |
| first_indexed | 2024-03-07T17:38:46Z |
| format | Article |
| id | doaj.art-2afb00dd500c48f4976c29a1434a3730 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:36Z |
| publishDate | 2020-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2afb00dd500c48f4976c29a1434a37302024-10-28T08:54:24ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-02-0112311210.15252/emmm.201911589Metabolic effects of bezafibrate in mitochondrial diseaseHannah Steele0Aurora Gomez‐Duran1Angela Pyle2Sila Hopton3Jane Newman4Renae J Stefanetti5Sarah J Charman6Jehill D Parikh7Langping He8Carlo Viscomi9Djordje G Jakovljevic10Kieren G Hollingsworth11Alan J Robinson12Robert W Taylor13Leonardo Bottolo14Rita Horvath15Patrick F Chinnery16Institute of Genetic Medicine, Newcastle UniversityDepartment of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical CampusInstitute of Genetic Medicine, Newcastle UniversityWellcome Centre for Mitochondrial Research, Newcastle UniversityWellcome Centre for Mitochondrial Research, Newcastle UniversityInstitute of Neuroscience, Newcastle UniversityInstitute of Cellular Medicine, Newcastle UniversityInstitute of Cellular Medicine, Newcastle UniversityWellcome Centre for Mitochondrial Research, Newcastle UniversityMRC Mitochondrial Biology Unit, University of CambridgeInstitute of Cellular Medicine, Newcastle UniversityInstitute of Cellular Medicine, Newcastle UniversityMRC Mitochondrial Biology Unit, University of CambridgeWellcome Centre for Mitochondrial Research, Newcastle UniversityDepartment of Medical Genetics, University of CambridgeDepartment of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical CampusDepartment of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical CampusAbstract Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open‐label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600–1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV‐immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF‐21), growth and differentiation factor 15 (GDF‐15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long‐term sequelae.https://doi.org/10.15252/emmm.201911589bezafibratemetabolomicsmitochondrial disordermitochondrial DNAmitochondrial encephalomyopathy |
| spellingShingle | Hannah Steele Aurora Gomez‐Duran Angela Pyle Sila Hopton Jane Newman Renae J Stefanetti Sarah J Charman Jehill D Parikh Langping He Carlo Viscomi Djordje G Jakovljevic Kieren G Hollingsworth Alan J Robinson Robert W Taylor Leonardo Bottolo Rita Horvath Patrick F Chinnery Metabolic effects of bezafibrate in mitochondrial disease EMBO Molecular Medicine bezafibrate metabolomics mitochondrial disorder mitochondrial DNA mitochondrial encephalomyopathy |
| title | Metabolic effects of bezafibrate in mitochondrial disease |
| title_full | Metabolic effects of bezafibrate in mitochondrial disease |
| title_fullStr | Metabolic effects of bezafibrate in mitochondrial disease |
| title_full_unstemmed | Metabolic effects of bezafibrate in mitochondrial disease |
| title_short | Metabolic effects of bezafibrate in mitochondrial disease |
| title_sort | metabolic effects of bezafibrate in mitochondrial disease |
| topic | bezafibrate metabolomics mitochondrial disorder mitochondrial DNA mitochondrial encephalomyopathy |
| url | https://doi.org/10.15252/emmm.201911589 |
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