Teriflunomide preserves peripheral nerve mitochondria from oxidative stress-mediated alterations

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.

Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress

“…In this context, we have investigated the therapeutic potential of the DHODH inhibitor TFN, an approved drug for the treatment of RRMS [19,20], on both neuronal and mitochondrial protection. Using a model in peripheral root explants, we have previously shown that mitochondria become shorter and rounder, and were less motile, during oxidative stress [28,30]. Importantly, using this model of peripheral nerves, we recently demonstrated that TFN could prevent the morphologic alterations of axonal mitochondria caused by oxidative stress [28].…”

“…We have shown previously that in peripheral nerves, mitochondria exposed to oxidative stress are affected even prior to the axonal damages [28,30] and that TFN prevents these mitochondrial alterations [28]. To monitor how TFN affects changes of mitochondria morphology during oxidative stress within the CNS, hippocampal slices from transgenic Tg(Thy1-CFP/COX8A)S2Lich/J mice (mitoCFP mice) that express cyan fluorescence protein (CFP) in neuronal mitochondria were imaged before (baseline image) and after the treatment with H 2 O 2 or H 2 O 2 + TFN.…”

“…We have shown previously that in peripheral nerves, mitochondria exposed to oxidative stress are affected even prior to the axonal damages [28,30] and that TFN prevents these mitochondrial alterations [28]. To monitor how TFN affects changes of mitochondria morphology during oxidative stress within the CNS, hippocampal slices from transgenic…”

“…Recently, we showed that TFN could prevent alterations in mitochondrial morphology, motility, as well as oxidation potential in peripheral spinal root explants during oxidative stress [28]. Considering the central role of inflammation-mediated oxidative stress and subsequent mitochondria damage in MS, we aimed here to determine whether TFN may also affect mitochondrial functionality and dynamics in hippocampal brain slices, which retain the complexity and physiology of central nervous system (CNS) structures and were exposed to oxidative stress conditions [29].…”

The Mitochondria-Independent Cytotoxic Effect of Leflunomide on RPMI-8226 Multiple Myeloma Cell Line

“…However, there were no symptoms of oxidative stress in teriflunomide treated cells. Despite this fact, there have been several reports of oxidative stress reduction—e.g., in fetal human pulmonary arterial endothelial cells due teriflunomide treatment [ 34 ]—and its ability to preserve peripheral nerve mitochondria from oxidative stress [ 35 ].…”