Mitochondrial and Metabolic Dysfunction of Peripheral Immune Cells in Multiple Sclerosis: An In-Depth Review

Multiple sclerosis (MS) is a chronic autoimmune disorder marked by inflammation and demyelination of the central nervous system (CNS). The exact mechanisms behind MS are not entirely understood, but mitochondrial dysfunction within immune cells is increasingly recognized as a significant factor. This comprehensive review by Wang et al., published in the Journal of Neuroinflammation (2024), delves into the intricate connections between mitochondrial abnormalities and MS, highlighting potential therapeutic targets and future research directions.

MS Pathophysiology and Immune Cell Involvement
MS is characterized by the progressive neurodegeneration and immune-mediated destruction of myelin in the CNS. It manifests primarily in three clinical forms: relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS). The autoimmune response in MS involves various immune cells, including T cells, B cells, macrophages (Mφ), and dendritic cells (DCs), each exhibiting distinct metabolic and mitochondrial dysfunctions.

Role of Mitochondria in Immune Cells
Mitochondria are pivotal in cellular respiration, ATP production, and regulation of apoptosis. In MS, mitochondrial dysfunction contributes to immune dysregulation and neurodegeneration. Key findings in the review include:

T Cells: MS patients' T cells show altered mitochondrial structure, reduced oxidative phosphorylation (OXPHOS), and increased reactive oxygen species (ROS) production. Treatments like interferon-beta and teriflunomide can modulate these dysfunctions, potentially restoring normal metabolic activity.

B Cells: These cells are crucial in antigen presentation and antibody production. In MS, B cells exhibit increased mitochondrial damage and altered cholesterol metabolism. Therapeutic interventions targeting mitochondrial respiration and glycolysis, such as BTK inhibitors, show promise in reducing B cell activation.

Monocytes and Macrophages: Monocytes in MS patients display heightened glycolysis and ROS production. Treatments targeting these pathways, like 2-deoxy-glucose (2-DG) and DMF, can shift monocytes towards an anti-inflammatory phenotype, reducing disease severity.

Dendritic Cells: DCs are vital for T cell activation and differentiation. Mitochondrial dysfunction in DCs can exacerbate autoimmune responses. Therapies like DMF that modulate oxidative stress and mitochondrial activity show potential in regulating DC function.

Therapeutic Implications
The review emphasizes the importance of targeting mitochondrial dysfunction in MS therapy. Current disease-modifying therapies (DMTs) such as interferon-beta, DMF, and teriflunomide impact mitochondrial functions across various immune cells, contributing to their therapeutic effects. Future research should focus on developing precision medicines that specifically address mitochondrial metabolic cascades.

Conclusion
The intricate relationship between mitochondrial dysfunction and immune cell activity in MS offers valuable insights into the disease's pathogenesis and potential treatment strategies. By understanding and targeting these metabolic abnormalities, new therapeutic avenues can be explored, potentially improving outcomes for individuals with MS.

References
Wang, P. F., Jiang, F., Zeng, Q. M., Yin, W. F., Hu, Y. Z., Li, Q., & Hu, Z. L. (2024). Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis. Journal of neuroinflammation, 21(1), 28.