Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed.

Keywords: Immune cells; Immune-metabolic; MS; Mitochondrion.

Fig. 1

Pathological manifestations of peripheral immune cells in MS. The pathogenesis of MS goes through three main phases: the autoimmune response (A), the chronic inflammatory response (B), and the demyelinating reaction (C). During the autoimmune reaction stage (A), various immune cells, such as T cells, B cells, and myelin-specific CD4⁺ T cells, penetrate the brain tissue through the blood–brain barrier (BBB). In the chronic inflammatory response (B), adaptive Th cells, Treg, and B cells release cytokines or interferon-γ and antibodies to contribute to the inflammatory response. Additionally, innate immune macrophages (Mϕ), and natural killer (NK) cells secrete substances like histamine, trypsin, ROS, NO, inflammatory cytokines, and Granzyme B, which participate in the inflammatory response. Peripheral immune cells, particularly T cells, B cells, monocytes and Mϕ, contribute to the demyelination process in MS through direct interactions with oligodendrocytes, the release of pro-inflammatory molecules, and the production of antibodies against myelin proteins. MS monocytes inhibit the phagocytic capacity of myeline debris, whereas exosomes derived from DCs promote myelination (C)

Fig. 2

Mitochondria in MS CD4⁺ T cells. CD4⁺ T cells boost the expression of glucose transporter (GLUT)1, resulting in enhanced glucose uptake and lactate generation, which can be blocked by 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) inhibitors. The deletion of acetyl-CoA carboxylase 1 (ACC1) reduces the synthesis of de novo fatty acids, decreases IFN-γ⁺ Th17 via the glycolytic-lipogenic pathway, and increases Foxp3⁺ Treg. Pentanoate acts on acetyl-CoA through the mTOR pathway, leading to increased glucose oxidation, secretion of IL-10, and inhibition of IL-17A production. Oleic acid restores the inhibitory state of CD4⁺ to Treg by promoting fatty acid β-oxidation. Pik3c3 increasing and Nur77 deleting both contribute to the elevation of mitochondrial extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Upregulation of mEF-G1 caused electron transport chain (ETC) assembly in mitochondria, and then elevated NAD⁺/NADH ratio. Above three mechanisms enhance Th1 or Th17 differentiation. Additionally, increased mitochondrial ROS can promote Th17 differentiation. Upregulated mitochondrial oxidative phosphorylation (OXPHOS) influences basic leucine zipper transcription factor TF-like (BATF), promoting Th17 differentiation and inhibiting Treg differentiation. DMF as well as the Bim and Bad pathways of phospholipids (PLs) treatment induces increased apoptosis by augmenting mitochondrial ROS production

Fig. 3

Mitochondria in MS monocytes. Upregulated pyruvate is converted to enormous lactate by increased expression of lactate dehydrogenase A (LDHA) enzyme in MS monocytes. The 2-deoxy-glucose (2-DG) inhibits glycolysis and reduces glucose uptake as well as lactate production. When monocytes are exposed to cerebrospinal fluid (CSF) from MS patients, there is an increase in the production of intracellular glutamine, pyruvate and extracellular glutamine, lactate and pyruvate. While the production of glutamic acid decreases. The small molecule inhibitor 6877002 inhibits the upregulated ROS, extracellular IL-6, tumor necrosis factor (TNF), and decreases IL-10 through the CD40-TRAF6 pathway. MS patients who respond IFN-β treatment alter in electron transport chain (ETC)-related genes, a mildly decrease ROS, and an improvement in mitochondrial dysfunction

Fig. 4

Mitochondria in MS Mϕ. The upregulated glucose transporters (GLUTs) (GLUT1, GLUT3, GLUT4) and monocarboxylate transporter 1 (MCT-1) of Mϕ in patients with MS enhance glycolysis. lactate dehydrogenase A (LDHA)and MCT-4 accumulation in Mϕ also lead to increased lactate production. The 3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid (FX11) as well as α-cyano-4-hydroxy-cinnamic acid (CHCA) can reduce lactate production and inflammatory activity. Fibrin induces an increase in p47phox leading to upregulate production of ROS. This is accompanied by elevated release of iron, resulting in axonal degeneration, demyelination and mitochondrial damage. Treatment with DMF or FhHDM-1 can inhibit glycolysis and enhance oxidative phosphorylation (OXPHOS), bringing about decreasing antigen-presenting function and inflammatory mediators such as ROS, IL-6, et al. in MS Mϕ