# Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders

## TL;DR

This review explores how dimethyl fumarate affects mitochondria in different cell types, highlighting its potential for treating neurological disorders.

## Contribution

The paper provides a comprehensive overview of dimethyl fumarate's cell-type-specific effects on mitochondrial physiology.

## Key findings

- DMF activates the Nrf2 pathway, increasing antioxidant enzymes and mitochondrial biogenesis markers.
- DMF enhances respiratory function in neurons and oligodendrocytes while reducing apoptosis.
- DMF can impair mitochondrial respiration in microglia and T cells under inflammatory stress.

## 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.

DMF modulates various biological phenomena related to mitochondrial physiology. This drug can increase or decrease mitochondrial activity, both effects being of pharmacological interest. Furthermore, DMF alters mitochondrial redox biology, potentially promoting or attenuating the production of reactive radical and non-radical species in these organelles. DMF also induces mitochondrial biogenesis (i.e., synthesis of new mitochondria) and mitophagy (i.e., degradation of mitochondria), depending on the context. However, it is known that DMF can act as a mitochondrial toxicant, promoting deleterious effects in healthy cells. Cell fate is modulated by DMF through a mitochondria-dependent action. Although much is known about the mechanisms of action by which DMF interferes with mitochondrial physiology, much remains to be discovered, which may allow this drug to be used in other clinical conditions in which mitochondria play a pathophysiological role. This figure was created by utilizing an image obtained from Servier Medical Art, licensed under a Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/).Diagram showing a central mitochondrion illustration surrounded by six labeled boxes: Mitochondrial function, Mitochondrial intoxication, Mitophagy, Intrinsic apoptotic pathway, Mitochondrial biogenesis, and Mitochondrial redox biology. An arrow points from a chemical structure toward the mitochondrion.

DMF modulates various biological phenomena related to mitochondrial physiology. This drug can increase or decrease mitochondrial activity, both effects being of pharmacological interest. Furthermore, DMF alters mitochondrial redox biology, potentially promoting or attenuating the production of reactive radical and non-radical species in these organelles. DMF also induces mitochondrial biogenesis (i.e., synthesis of new mitochondria) and mitophagy (i.e., degradation of mitochondria), depending on the context. However, it is known that DMF can act as a mitochondrial toxicant, promoting deleterious effects in healthy cells. Cell fate is modulated by DMF through a mitochondria-dependent action. Although much is known about the mechanisms of action by which DMF interferes with mitochondrial physiology, much remains to be discovered, which may allow this drug to be used in other clinical conditions in which mitochondria play a pathophysiological role. This figure was created by utilizing an image obtained from Servier Medical Art, licensed under a Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/).