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

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 mitoch...

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Veröffentlicht in:	Human molecular genetics Jg. 26; H. 15; S. 2864
Hauptverfasser:	Hayashi, Genki, Jasoliya, Mittal, Sahdeo, Sunil, Saccà, Francesco, Pane, Chiara, Filla, Alessandro, Marsili, Angela, Puorro, Giorgia, Lanzillo, Roberta, Brescia Morra, Vincenzo, Cortopassi, Gino
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England 01.08.2017
Schlagworte:	Animals Cell Culture Techniques Dimethyl Fumarate - chemistry Dimethyl Fumarate - metabolism Fibroblasts Humans Mice Mitochondria - metabolism Multiple Sclerosis - metabolism Multiple Sclerosis - pathology Neuroprotective Agents - pharmacology NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Organelle Biogenesis
ISSN:	1460-2083, 1460-2083
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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.
AbstractList	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.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. 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.
Author	Filla, Alessandro Lanzillo, Roberta Saccà, Francesco Jasoliya, Mittal Brescia Morra, Vincenzo Hayashi, Genki Cortopassi, Gino Marsili, Angela Puorro, Giorgia Sahdeo, Sunil Pane, Chiara
Author_xml	– sequence: 1 givenname: Genki surname: Hayashi fullname: Hayashi, Genki organization: Department of Molecular Biosciences, University of California, Davis, 95616 CA, USA – sequence: 2 givenname: Mittal surname: Jasoliya fullname: Jasoliya, Mittal organization: Department of Molecular Biosciences, University of California, Davis, 95616 CA, USA – sequence: 3 givenname: Sunil surname: Sahdeo fullname: Sahdeo, Sunil organization: Janssen Pharmaceuticals, 3210 Merryfield Row, San Diego, 92121 CA, USA – sequence: 4 givenname: Francesco surname: Saccà fullname: Saccà, Francesco organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 5 givenname: Chiara surname: Pane fullname: Pane, Chiara organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 6 givenname: Alessandro surname: Filla fullname: Filla, Alessandro organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 7 givenname: Angela surname: Marsili fullname: Marsili, Angela organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 8 givenname: Giorgia surname: Puorro fullname: Puorro, Giorgia organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 9 givenname: Roberta surname: Lanzillo fullname: Lanzillo, Roberta organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 10 givenname: Vincenzo surname: Brescia Morra fullname: Brescia Morra, Vincenzo organization: Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II, Naples 80131, Italy – sequence: 11 givenname: Gino surname: Cortopassi fullname: Cortopassi, Gino organization: Department of Molecular Biosciences, University of California, Davis, 95616 CA, USA
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Snippet	The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF)...
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SubjectTerms	Animals Cell Culture Techniques Dimethyl Fumarate - chemistry Dimethyl Fumarate - metabolism Fibroblasts Humans Mice Mitochondria - metabolism Multiple Sclerosis - metabolism Multiple Sclerosis - pathology Neuroprotective Agents - pharmacology NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Organelle Biogenesis
Title	Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans
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