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Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders
Marcos Roberto de Oliveira1,2,3,4
1Grupo de Estudos em Neuroquímica e Neurobiologia de Moléculas Bioativas, Departamento de Química, Universidade Federal de Mato Grosso (UFMT), Cuiaba, Mato Grosso, Brazil.
Abstract:
Dimethyl fumarate (DMF; C6H8O4) is an ester of fumaric acid widely used in clinical practice for the treatment of relapsing forms of multiple sclerosis and plaque psoriasis. Beyond its established immunomodulatory actions, DMF is increasingly recognized as a small molecule capable of reshaping cellular redox homeostasis and mitochondrial physiology. Mitochondria are double-membrane organelles that integrate energy metabolism, calcium buffering, and apoptosis regulation, while also generating reactive oxygen species that function as signaling mediators. Given their central role in neuronal survival and function, mitochondrial integrity is a critical determinant of neuroprotection. The aim of this review is to discuss the mechanistic aspects by which DMF influences mitochondrial physiology in central nervous system (CNS) cells, based on evidence from experimental models and patient-derived samples. Data consistently show that DMF activates the Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., NQO-1, HO-1) and induction of mitochondrial biogenesis markers (e.g., PGC-1α, NRF1, TFAM). In neurons and oligodendrocytes, DMF enhances respiratory function and limits apoptosis by modulating BCL-2 family proteins and suppressing cytochrome c release. Disease-relevant studies further demonstrate frataxin upregulation in Friedreich's ataxia and reduction of mitochondrial reactive oxygen species in C9orf72-related models. Conversely, in microglia, T cells, and vascular cells, DMF may impair mitochondrial respiration or increase apoptosis, particularly under inflammatory stress, suggesting a context-dependent effect. In conclusion, DMF exerts multifaceted and cell type-specific actions on mitochondria. Understanding these mechanisms may guide optimized therapeutic strategies and the identification of biomarkers for precision use in neurological disorders.
Insights
Dimethyl fumarate (DMF) impacts mitochondria differently across cell types. It boosts antioxidant defenses and mitochondrial function in neurons but may impair them in immune and vascular cells, suggesting tailored therapeutic uses for neurological disorders.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pharmacology
Background:
- Dimethyl fumarate (DMF) is a drug used for multiple sclerosis and psoriasis.
- DMF influences cellular redox balance and mitochondrial function.
- Mitochondria are crucial for neuronal survival and function.
Purpose of the Study:
- To review how DMF affects mitochondrial physiology in central nervous system (CNS) cells.
- To explore DMF's mechanisms based on experimental and patient data.
Main Methods:
- Review of experimental models and patient-derived samples.
- Analysis of DMF's effects on Nrf2 pathway activation.
- Assessment of mitochondrial respiration, apoptosis, and specific protein expression.
Main Results:
- DMF activates the Nrf2 pathway, increasing antioxidant enzymes and mitochondrial biogenesis markers.
- In neurons and oligodendrocytes, DMF improves respiratory function and reduces apoptosis.
- DMF shows context-dependent effects, potentially impairing mitochondria in immune and vascular cells under inflammatory stress.
Conclusions:
- DMF has diverse, cell-type-specific effects on mitochondria.
- Understanding these mechanisms can inform precision medicine for neurological disorders.
- Further research may identify biomarkers for DMF's therapeutic use.
