Neurodegeneration in Multiple Sclerosis: The Role of Nrf2-Dependent Pathways

Abstract

Multiple sclerosis (MS) encompasses a chronic, irreversible, and predominantly immune-mediated disease of the central nervous system that leads to axonal degeneration, neuronal death, and several neurological symptoms. Although various immune therapies have reduced relapse rates and the severity of symptoms in relapsing-remitting MS, there is still no cure for this devastating disease. In this brief review, we discuss the role of mitochondria dysfunction in the progression of MS, focused on the possible role of Nrf2 signaling in orchestrating the impairment of critical cellular and molecular aspects such as reactive oxygen species (ROS) management, under neuroinflammation and neurodegeneration in MS. In this scenario, we propose a new potential downstream signaling of Nrf2 pathway, namely the opening of hemichannels and pannexons. These large-pore channels are known to modulate glial/neuronal function and ROS production as they are permeable to extracellular Ca²⁺ and release potentially harmful transmitters to the synaptic cleft. In this way, the Nrf2 dysfunction impairs not only the bioenergetics and metabolic properties of glial cells but also the proper antioxidant defense and energy supply that they provide to neurons.

Keywords: Nrf2-dependent pathways; glial cells; mitochondria; multiple sclerosis; neuroinflammation; pannexin-1; reactive oxygen species.

Figure 1

Mitochondrial dysfunction in MS progression. Mitochondria are essential for neuronal function by maintaining bioenergetics through the synthesis of ATP in the electron transport chain (ETC) and by supporting neuron-to-neuron communication by governing [Ca²⁺]_i in the presynaptic compartment and then facilitating neurotransmitters release. During MS, the neuroinflammatory environment that characterizes demyelination, i.e., increased ROS levels along with the release of proinflammatory cytokines by glial cells, leads to impaired mitochondrial dynamics, alterations in the synthesis of ATP due to decreases in the expressions of ETC complexes 1 and 4, and decreases in the mitochondria content at presynaptic level, impairing neuronal survival and communication (for details, see the main text). This figure was created in Biorender.

Figure 2

Nrf2 response to oxidative stress. Under an oxidative environment, Keap1 releases Nrf2, which translocates from the cytoplasm to the nucleus, where it binds to the ARE sequence, activating the anti-inflammatory response elements (ARE) pathway. This pathway allows for the transcription of genes that code for the main antioxidant enzymes, which will modulate mitochondrial damage by decreasing ROS and facilitating ATP synthesis. HO-1: heme oxygenase-1. NQO1: H quinone oxidoreductase-1. GST: glutathione S-transferase. GCL: glutamate-cysteine ligase. GPx: glutathione peroxidase. This figure was created in Biorender.

Figure 3

The impact of impaired Nrf2 pathway on glial large pore channels during MS. Under neuroinflammatory conditions, the increase in ROS triggers typically the activation of the Nrf2 transcription factor in glial cells (such as astrocytes and microglia), inducing the anti-inflammatory response element (ARE) pathway activation that finally restore the ROS levels. In these conditions, Nrf2 maintains an inhibitory tone on Cx43 hemichannels, keeping their activity in a physiological range. In contrast, during MS the proper function of the Nrf2 transcription factor is impaired, which result in decreased activation of ARE pathways accompanied of persistent and exacerbated opening of large pore channels, including Cx43 hemichannels and likely Panx1 channels in glial cells (see the main text). This figure was created in Biorender.