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Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans
Genki Hayashi1, Mittal Jasoliya1, Sunil Sahdeo2
1Department of Molecular Biosciences, University of California, Davis, 95616 CA, USA.
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.
Insights
Dimethyl fumarate (DMF) boosts mitochondrial biogenesis and function in cells, mice, and humans, primarily via Nrf2. This finding offers potential new therapies for mitochondrial and muscle diseases, including Multiple Sclerosis.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Mitochondrial dysfunction is implicated in various diseases.
- Mitochondrial biogenesis is a key process for cellular energy production.
- Therapeutic strategies to enhance mitochondrial function are needed.
Purpose of the Study:
- To investigate the effect of dimethyl fumarate (DMF) on mitochondrial biogenesis and function.
- To determine the molecular targets of DMF in inducing mitochondrial biogenesis.
- To explore the potential of DMF as a therapeutic agent for mitochondrial and muscle diseases.
Main Methods:
- In vitro cell culture experiments.
- In vivo studies in mice.
- Human dosing studies.
- Analysis of gene expression related to mitochondrial function.
- Assessment of hydroxycarboxylic acid receptor 2 (HCAR2) and Nrf2 pathways.
Main Results:
- DMF dose-dependently induced mitochondrial biogenesis and function in cells, mice, and humans.
- Nrf2 was identified as the primary target of DMF in inducing mitochondrial gene expression.
- This is the first drug shown to increase mitochondrial biogenesis through in vivo human dosing.
- Mitochondrial biogenesis was found to be deficient in Multiple Sclerosis patients.
Conclusions:
- DMF effectively induces mitochondrial biogenesis and function via the Nrf2 pathway.
- DMF represents a potential therapeutic candidate for mitochondrial and muscle diseases.
- The deficiency in mitochondrial biogenesis in Multiple Sclerosis suggests new therapeutic avenues for MS.
