Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans

Genki Hayashi, Mittal Jasoliya, Sunil Sahdeo, Francesco Saccà, Chiara Pane, Alessandro Filla, Angela Marsili, Giorgia Puorro, Roberta Lanzillo, Vincenzo Brescia Morra, Gino A Cortopassi

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.

Original languageEnglish (US)
Pages (from-to)2864-2873
Number of pages10
JournalHuman Molecular Genetics
Volume26
Issue number15
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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Organelle Biogenesis
Mitochondrial Diseases
Mitochondrial Genes
Gene Expression
Muscles
Multiple Sclerosis
Dimethyl Fumarate
Therapeutics
Acids
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. / Hayashi, Genki; Jasoliya, Mittal; Sahdeo, Sunil; Saccà, Francesco; Pane, Chiara; Filla, Alessandro; Marsili, Angela; Puorro, Giorgia; Lanzillo, Roberta; Brescia Morra, Vincenzo; Cortopassi, Gino A.

In: Human Molecular Genetics, Vol. 26, No. 15, 01.08.2017, p. 2864-2873.

Research output: Contribution to journalArticle

Hayashi, G, Jasoliya, M, Sahdeo, S, Saccà, F, Pane, C, Filla, A, Marsili, A, Puorro, G, Lanzillo, R, Brescia Morra, V & Cortopassi, GA 2017, 'Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans', Human Molecular Genetics, vol. 26, no. 15, pp. 2864-2873. https://doi.org/10.1093/hmg/ddx167
Hayashi G, Jasoliya M, Sahdeo S, Saccà F, Pane C, Filla A et al. Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Human Molecular Genetics. 2017 Aug 1;26(15):2864-2873. https://doi.org/10.1093/hmg/ddx167
Hayashi, Genki ; Jasoliya, Mittal ; Sahdeo, Sunil ; Saccà, Francesco ; Pane, Chiara ; Filla, Alessandro ; Marsili, Angela ; Puorro, Giorgia ; Lanzillo, Roberta ; Brescia Morra, Vincenzo ; Cortopassi, Gino A. / Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 15. pp. 2864-2873.
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