Metabolic effects of bezafibrate in mitochondrial disease

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

doi:10.15252/emmm.201911589

Metabolic effects of bezafibrate in mitochondrial disease

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

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

64 Downloads (Pure)

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.

Original language	English
Article number	e11589
Number of pages	12
Journal	EMBO Molecular Medicine
Volume	12
Issue number	3
Early online date	28 Feb 2020
DOIs	https://doi.org/10.15252/emmm.201911589
Publication status	Published - 6 Mar 2020
Externally published	Yes

Bibliographical note

© 2020 The Authors. Published under the terms of the CC BY 4.0 license.

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Funder

PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Evelyn Trust and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. RWT is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the UK National Institute for Health Research Biomedical Research Centre in Age and Age‐Related Diseases award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, the MRC/EPSRC Molecular Pathology Node and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. RH is a Wellcome Senior Investigator (109915/Z/15/Z) and supported by the Medical Research Council (UK) (MR/N025431/1), the Newton Fund (UK/Turkey, MR/N027302/1), the European Research Council (309548) and the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z). LB is supported by The Alan Turing Institute under the Engineering and Physical Sciences Research Council grant EP/N510129/1.

Keywords

bezafibrate
metabolomics
mitochondrial DNA
mitochondrial disorder
mitochondrial encephalomyopathy

ASJC Scopus subject areas

Molecular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.15252/emmm.201911589Licence: CC BY

PublishedFinal published version, 1.4 MBLicence: CC BY

Cite this

Steele, H., Gomez-Duran, A., Pyle, A., Hopton, S., Newman, J., Stefanetti, R. J., Charman, S. J., Parikh, J. D., He, L., Viscomi, C., Jakovljevic, D. G., Hollingsworth, K. G., Robinson, A. J., Taylor, R. W., Bottolo, L., Horvath, R., & Chinnery, P. F. (2020). Metabolic effects of bezafibrate in mitochondrial disease. EMBO Molecular Medicine, 12(3), Article e11589. https://doi.org/10.15252/emmm.201911589

Steele, H, Gomez-Duran, A, Pyle, A, Hopton, S, Newman, J, Stefanetti, RJ, Charman, SJ, Parikh, JD, He, L, Viscomi, C, Jakovljevic, DG, Hollingsworth, KG, Robinson, AJ, Taylor, RW, Bottolo, L, Horvath, R & Chinnery, PF 2020, 'Metabolic effects of bezafibrate in mitochondrial disease', EMBO Molecular Medicine, vol. 12, no. 3, e11589. https://doi.org/10.15252/emmm.201911589

@article{e987b8201fba4a889a824f684cae4bb0,

title = "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 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.",

keywords = "bezafibrate, metabolomics, mitochondrial DNA, mitochondrial disorder, mitochondrial encephalomyopathy",

author = "Hannah Steele and Aurora Gomez-Duran and Angela Pyle and Sila Hopton and Jane Newman and Stefanetti, {Renae J} and Charman, {Sarah J} and Parikh, {Jehill D} and Langping He and Carlo Viscomi and Jakovljevic, {Djordje G} and Hollingsworth, {Kieren G} and Robinson, {Alan J} and Taylor, {Robert W} and Leonardo Bottolo and Rita Horvath and Chinnery, {Patrick F}",

note = "{\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",

year = "2020",

month = mar,

day = "6",

doi = "10.15252/emmm.201911589",

language = "English",

volume = "12",

journal = "EMBO Molecular Medicine",

issn = "1076-1551",

publisher = "Feinstein Institute for Medical Research",

number = "3",

}

TY - JOUR

T1 - Metabolic effects of bezafibrate in mitochondrial disease

AU - Steele, Hannah

AU - Gomez-Duran, Aurora

AU - Pyle, Angela

AU - Hopton, Sila

AU - Newman, Jane

AU - Stefanetti, Renae J

AU - Charman, Sarah J

AU - Parikh, Jehill D

AU - He, Langping

AU - Viscomi, Carlo

AU - Jakovljevic, Djordje G

AU - Hollingsworth, Kieren G

AU - Robinson, Alan J

AU - Taylor, Robert W

AU - Bottolo, Leonardo

AU - Horvath, Rita

AU - Chinnery, Patrick F

N1 - © 2020 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2020/3/6

Y1 - 2020/3/6

N2 - 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.

AB - 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.

KW - bezafibrate

KW - metabolomics

KW - mitochondrial DNA

KW - mitochondrial disorder

KW - mitochondrial encephalomyopathy

UR - http://www.scopus.com/inward/record.url?scp=85081203922&partnerID=8YFLogxK

U2 - 10.15252/emmm.201911589

DO - 10.15252/emmm.201911589

M3 - Article

C2 - 32107855

SN - 1076-1551

VL - 12

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 3

M1 - e11589

ER -

Metabolic effects of bezafibrate in mitochondrial disease

Abstract

Bibliographical note

Funder

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Djordje Jakovljevic

Cite this

Metabolic effects of bezafibrate in mitochondrial disease

Abstract

Bibliographical note

Funder

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Profiles

Djordje Jakovljevic

Cite this