Metabolic effects of bezafibrate in mitochondrial disease

• Published in: EMBO molecular medicine 2020-03, Vol.12 (3), p.e11589-n/a
• Main Authors: Steele, Hannah, Gomez‐Duran, Aurora, Pyle, Angela, Hopton, Sila, Newman, Jane, Stefanetti, Renae J, Charman, Sarah J, Parikh, Jehill D, He, Langping, Viscomi, Carlo, Jakovljevic, Djordje G, Hollingsworth, Kieren G, Robinson, Alan J, Taylor, Robert W, Bottolo, Leonardo, Horvath, Rita, Chinnery, Patrick F
• Format: Article
• Language: English
• Subjects: Amino acids; Animal models; Bezafibrate; Bezafibrate - pharmacology; Biomarkers; Biosynthesis; Body mass index; Complications; Diabetes; Disease; EMBO08; EMBO16; EMBO21; Evolution; Fibroblast growth factors; Humans; Hypoglycemia; Immunodeficiency; Liver; Metabolism; Metabolites; Metabolomics; Mitochondria; Mitochondria - metabolism; mitochondrial disorder; Mitochondrial DNA; mitochondrial encephalomyopathy; Mitochondrial Myopathies - drug therapy; Mitochondrial Myopathies - metabolism; Mutation; Myopathy; Organelle Biogenesis; Patients; Studies
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201911589

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. Synopsis There are currently no treatments for mitochondrial disorders. Bezafibrate has been shown to induce mitochondrial biogenesis and improve mitochondrial function in pre‐clinical models, but has not been systematically studied in patients. We performed an open‐label observational study of six patients with the m.3243A>G MTTL1 mutation using 600–1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events. We observed an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF‐21), growth and differentiation factor 15 (GDF‐15). Metabolomic analysis showed dysregulation of fatty‐acid and amino‐acid metabolism, which are signs of compromised oxidative phosphorylation. Although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate worsened the metabolomic signature of mitochondrial disease, raising concerns about long‐term sequalae. Graphical Abstract There are currently no treatments for mitochondrial disorders. Bezafibrate has been shown to induce mitochondrial biogenesis and improve mitochondrial function in pre‐clinical models, but has not been systematically studied in patients.