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Teriflunomide preserves peripheral nerve mitochondria from oxidative stress-mediated alterations

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Item Type:Article
Title:Teriflunomide preserves peripheral nerve mitochondria from oxidative stress-mediated alterations
Creators Name:Malla, B. and Cotten, S. and Ulshoefer, R. and Paul, F. and Hauser, A.E. and Niesner, R. and Bros, H. and Infante-Duarte, C.
Abstract:Mitochondrial dysfunction is a common pathological hallmark in various inflammatory and degenerative diseases of the central nervous system, including multiple sclerosis (MS). We previously showed that oxidative stress alters axonal mitochondria, limiting their transport and inducing conformational changes that lead to axonal damage. Teriflunomide (TFN), an oral immunomodulatory drug approved for the treatment of relapsing forms of MS, reversibly inhibits dihydroorotate dehydrogenase (DHODH). DHODH is crucial for de novo pyrimidine biosynthesis and is the only mitochondrial enzyme in this pathway, thus conferring a link between inflammation, mitochondrial activity and axonal integrity. Here, we investigated how DHODH inhibition may affect mitochondrial behavior in the context of oxidative stress. We employed a model of transected murine spinal roots, previously developed in our laboratory. Using confocal live imaging of axonal mitochondria, we showed that in unmanipulated axons, TFN increased significantly the mitochondria length without altering their transport features. In mitochondria challenged with 50 µM hydrogen peroxide (H2O2) to induce oxidative stress, the presence of TFN at 1 µM concentration was able to restore mitochondrial shape, motility, as well as mitochondrial oxidation potential to control levels. No effects were observed at 5 µM TFN, while some shape and motility parameters were restored to control levels at 50 µM TFN. Thus, our data demonstrate an undescribed link between DHODH and mitochondrial dynamics and point to a potential neuroprotective effect of DHODH inhibition in the context of oxidative stress-induced damage of axonal mitochondria.
Keywords:Dihydroorotate Dehydrogenase (DHODH), Mitochondria, Mitochondrial Dynamics, Neurodegeneration, Oxidative Stress, Teriflunomide (TFN), Animals, Mice
Source:Therapeutic Advances in Chronic Disease
Publisher:Sage Publications
Page Range:1-14
Official Publication:https://doi.org/10.1177/2040622320944773
PubMed:View item in PubMed

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