Wang et al.

Journal of Neuroinflammation (2024) 21:28 Journal of Neuroinflammation

[Link]

REVIEW Open Access

Mitochondrial and metabolic dysfunction

of peripheral immune cells in multiple sclerosis
Peng‑Fei Wang1, Fei Jiang2, Qiu‑Ming Zeng2, Wei‑Fan Yin3, Yue‑Zi Hu4, Qiao Li1 and Zhao‑Lan Hu1*

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 mitochon‑
drial 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 Mitochondrion, Immune-metabolic, Immune cells, MS

Introduction secondary progressive (SPMS) and the primary progres-

Multiple sclerosis (MS) is a chronic multifocal demy- sive (PPMS) [3]. RRMS is the most common form, and
elinating neuroinflammatory disease characterized by it would experience unpredictable onset of neurologi-
progressive neurodegeneration and an autoimmune cal symptoms (relapses) and then complete or partially
response [1, 2]. According to the latest Multiple Sclero- recovery (remissions). Over time, relapsing–remitting
sis Atlas, 2.8 million people have MS worldwide [3]. MS attacks become less frequent and neurological function
occurs at a younger age compared to other neurological may gradually deteriorate to SPMS. On the other hand,
illnesses [4], with a mean age of diagnosis at 32 years. The PPMS patients do not experience attacks or remissions,
prevalence of MS is higher in females, with a female-to- and symptoms continually worsen [3].
male ratio of 3:1 [5]. MS can be divided into three clini- Currently, the diagnosis of MS primarily relies on mag-
cal manifestations: the relapsing–remitting (RRMS), the netic resonance imaging (MRI), which detects lesions in
two or more areas of the central nervous system (CNS)
along with corresponding clinical symptoms [6]. Cer-
*Correspondence: ebrospinal fluid (CSF) analysis and intrathecal immu-
Zhao‑Lan Hu
noglobulin G production can aid in the diagnosis [7, 8].
huzhaolan@[Link]
1
Department of Anesthesiology, The Second Xiangya Hospital, Central However, there has been currently no reliable or sensitive
South University, 139 Ren‑Min Central Road, Changsha City 410011, biomarker in peripheral blood to identify the condition.
Hunan, China
2 In addition, the majority of existing medications utilized
Department of Neurology, Xiangya Hospital, Central South University,
Changsha City 410011, Hunan, China for the treatment of MS primarily improve the patient’s
3
Department of Neurology, The Second Xiangya Hospital, Central South condition and slow the advancement of the disease.
University, 139 Ren‑Min Central Road, Changsha City 410011, Hunan,
Hence, it is imperative to identify early diagnostic mark-
China
4
Clinical Laboratory, The Second Hospital of Hunan University of Chinese ers for diagnosis and efficacious treatments.
Medicine, 233 Cai’ e North Road, Changsha City 410005, Hunan, China Genetic, environmental, and immune factors play sig-
nificant roles in the development of MS. More than 230

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Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 2 of 19

genetic variations associated with a higher risk of devel- in mitochondrial dynamics and changes in the TCA
oping MS have been identified [9, 10]. Genome-wide cycle; (5) initiating mitochondria-mediated apoptosis.
association studies (GWAS) provide biological insights Elevated glucose and lactate metabolism in active MS
into the genetic susceptibility of MS, suggesting that lesions have been revealed through investigations using
peripheral immune cells are essential mediators of dis- magnetic resonance spectroscopy and positron emis-
ease risk variants [11]. Some of these variants are related sion tomography imaging and immunohistochemistry
to the aspect of myelin structure or mitochondrial func- staining [30, 31]. Further evidence of increased metabolic
tion [12]. activity in active MS lesions is derived from the higher
A specific genetic factor strongly linked to MS develop- quantity and functioning of mitochondria in responsive
ment is a variation in the human leukocyte antigen com- axons [32]. In chronic inactive areas of MS lesions, both
plex known as HLA-DRB1*15:01. This variation plays a the activity of mitochondrial respiratory chain complex
significant role in antigen presentation by antigen-pre- IV and mitochondrial mass increase in demyelinated
senting cells (APCs) [10, 13]. Additionally, environmen- axons [33].
tal influences such as obesity, gut microbiota imbalance, This review summarized the immunological-metabolic
virus infection, and smoking contribute to increased risks mechanisms involved in mitochondrial dysfunction in
of developing MS, with Epstein–Barr virus (EBV) infec- peripheral immune cells associated with MS. The rela-
tion increasing the risk by 32-fold [14]. These factors tionship between MS and mitochondrial function is
may affect mitochondrial biogenesis and functions [15]. discussed, with a focus on disease-modifying therapies
Moreover, immune dysregulation in MS leads to the infil- (DMTs). The aim is to provide insightful hints for inves-
tration of immune cells into the CNS, triggering demy- tigating the mitochondrial immune function related to
elination, axonal damage, and neurodegeneration [16]. MS.
The primary target of immune cell attack is the myelin
sheath in the white matter of the CNS [17, 18]. Local The role of peripheral immune cells in MS
inflammation and demyelination lead to the diffusion pathology
of self-antigens, sequestration of myelin, and activation Autoimmune response
of autoreactive T lymphocytes [19, 20]. B cells primar- The autoimmune response is considered a key patho-
ily present self-antigens to T lymphocytes through the genic mechanisms underlying MS, wherein an abnormal
secretion of self-reactive antibodies [21]. Each immune immune response targets self-antigens within the CNS
cell type has a unique metabolic profile crucial for its [34]. This response is triggered by the activation of auto-
function and maintenance [22]. Understanding these reactive T cells and B cells, which recognize and attack
metabolic profiles may provide new insights into control- myelin and other components of the CNS [2, 35]. Acti-
ling the immune response in MS. vated myelin-specific ­CD4+ T cells that react to myelin
Mitochondria are double-membrane organelle in antigens are primarily responsible for this reaction [36].
eukaryotic cells and they are the main site of cellular Myelin antigens, together with HLA class II molecules
aerobic respiration. Mitochondria produce adenosine and accessory molecules on the surface of APCs, reac-
triphosphate (ATP) through oxidative phosphorylation, tivate ­CD4+ T cells in their native environment. The
which occurs in the inner mitochondrial membrane. The presence of autoantibodies against myelin proteins in
electron transport chain (ETC) complex in this process the serum and CSF of MS patients indicates that the
transfers electrons to O ­ 2 to form reactive oxygen spe- immune system perceives these proteins as foreign enti-
cies (ROS). Additionally, other mitochondrial processes ties and initiates an immune response against them. [37,
such as fatty acid metabolism and tricarboxylic acid cycle 38]. Additionally, the presence of inflammatory cells,
(TCA) can also promote ROS production. But if the pro- such as T cells and B cells within MS lesions demon-
duction of ROS exceeds the physiological limit, it can strates an ongoing immune response within the CNS
potentially damage cellular components [23]. Mitochon- [39]. Reactivation of MS triggers the release of inflamma-
dria also play a role in apoptosis, regulation of calcium tory cytokines and soluble mediators, which disrupts the
balance, production of mitochondrial DNA (mtDNA), blood–brain barrier (BBB), stimulates chemotaxis, and
oxidative phosphorylation (OXPHOS), and mitochon- leads to a larger-scale influx of inflammatory cells into
drial metabolism [24, 25]. Mitochondria significantly the CNS [40] (Fig. 1A). The experimental autoimmune
contribute to the pathogenesis of MS [26–29] by: (1) encephalomyelitis (EAE) model, induced by immunizing
accumulating mutations and repairing mtDNA dam- animals with myelin-derived proteins (or polypeptides),
age; (2) exhibiting abnormal mitochondrial protein or such as myelin oligodendrocyte glycoprotein (MOG),
gene expression; (3) displaying defects in mitochondrial proteolipid protein (PLP), and myelin basic protein
enzyme activity and aging; (4) experiencing disturbances (MBP), serves as a classic animal model of MS. EAE mice
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 3 of 19

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)
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 4 of 19

­ D4+ T
model is characterized by the myelin-reactive C inflammatory cytokines and chemokines that attract
cells and B cells [35, 41]. other immune cells to the site of inflammation, leading
to the further damage to the myelin sheath [54, 55]. In
Chronic inflammatory response progressive MS, cortical demyelination is associated both
The chronic inflammatory response in MS is character- with B cell-rich structures in the meninges and plasma
ized by the activation and proliferation of T cells, B cells, cell accumulation in experimental CNS inflammation
and other immune cells, resulting in the release of pro- [56–58], which may be involved in secretory products
inflammatory cytokines, chemokines, ROS and nitric independent of antibodies, and multiple cytokines pro-
oxide (NO) [16] (Fig. 1B). This chronic inflammation duced by B cells in progressive MS patients are cytotoxic
leads to the destruction of myelin, axons, and oligoden- to oligodendrocytes and neurons [59, 60]. On the other
drocytes, ultimately causing neurological dysfunction hand, autoreactive B cells can differentiate into plasma
and disability [42]. Recent studies have implicated the cells, producing antibodies that bind to the myelin sheath
innate immune system in the pathogenesis of MS. Acti- and oligodendrocyte proteins. These bound antibodies
vation of toll-like receptors (TLRs) activation leads to the result in the induction and activation of the complement
release of pro-inflammatory cytokines and chemokines, proteins on tissue surfaces, directly damaging the myelin
contributing to the chronic inflammatory response in MS sheath and exacerbating demyelination [61, 62]. Inflamed
[43]. Pro-inflammatory Th1 and Th17 have been associ- monocytes derived from individuals with MS exhibit a
ated with the pathology of MS [44]. On the contrary, reg- diminished ability to engulf and remove myelin debris,
ulatory T cell (Treg) mediates the dysregulation of T cell a process crucial for prompt and effective remyelination
response in MS by reducing their number and activity [63]. Mφ release a substantial quantity of cytokines and
[45, 46]. T cells and B cells can be detected in damaged NO, penetrating the CNS, which is a vital element in ini-
white and gray matter [47]. In MS, B cells differentiate tiating the demyelination response in MS [64]. Distinct
into memory cells or plasma cells, which subsequently subgroups of Mφ exert contrasting influences on myeli-
secrete autoantibodies involved in antibody-dependent nation, with inflammatory Mφ facilitating demyelination
cellular cytotoxicity and complement damage. B cells also [65] and immune-modulatory Mφ facilitating remyelina-
have the ability to secrete pro-inflammatory cytokines, tion [66]. Dendritic cells (DCs) culture stimulated with
including lymphotoxin (LT) and tumor necrosis factor low-level IFN-γ-released exosomes can increase myelina-
(TNF)-α, significantly contributing to T cell activation tion and reduce oxidative stress both in vitro and in vivo
[48]. Mucosal-associated invariant T (MAIT) cells, a sub- in EAE mice [67].
set of innate-like ­CD8+ T cells, express semi-invariant T
cell receptors as well as accumulate in the MS brain and The mitochondrial of peripheral immune cells
produce IL-17 [49]. Innate immunity involves mast cells, in MS
macrophages (Mφ) and natural killer (NK) cells. Mast Mitochondria in MS T cells
cells in MS plaques release histamine and trypsin simul- The modulation of T lymphocyte homeostasis in MS is
taneously to facilitate BBB opening [16]. Mφ produce influenced by mitochondrial involvement. Several mito-
cytokines such as interleukin (IL)-12, IL-23, and are also chondrial proteins, including B cell lymphoma 2 (Bcl2),
involved in the clearance of demyelinating debris [16]. ocular atrophy 1 (OPA1), prohibitin 2 (PHB2), Sirtuin-3
Some subgroups of microglia and Mφ produce TNF-α, (SIRT3), mitochondrial metalloendopeptidase OMA1,
ROS and NO in the activated state, exerting direct neu- and autophagy related 5 (ATG5), are closely associated
rotoxic effects. ­CD56bright NK cells promote the produc- with mitochondria-mediated death in MS T cells, prob-
tion of granzyme B, which is involved in cytotoxicity and ably caused by oxidative stress [29, 68–72]. Some studies
autologous ­CD4+ T cells proliferation [50]. have shown that T cells from MS patients exhibit altered
mitochondrial structure, reduced glycolysis, downregu-
Demyelination reaction lated expression and activity of OXPHOS subunits, and
Peripheral immune cells are activated and enter the CNS decreased mitochondrial membrane potential (MMP)
where they contribute to the destruction of the myelin [73–77]. Treatment with IFN beta-1α has the potential
sheath [51] (Fig. 1C). Myelin-specific T cells exacerbate to restore the diminished glycolysis and mitochondrial
demyelinating lesions in CNS autoimmunity by releasing respiration activity observed in T cells derived from
cytokines such as IL-17, interferon (IFN)-γ, and granu- patients with RRMS. This restorative effect is linked to
locyte macrophage-colony stimulating factor (GM-CSF) elevated levels of aldolase, hexokinase 1 (HK-1), enolase 1
[52, 53]. Besides, autoreactive T cells mistakenly target (ENO1), glucose transporter 1 (GLUT1), dihydrolipoam-
and attack myelin, which is the protective covering of ide-S-acetyl transferase (DLAT), and dihydrolipoamide-
nerve fibers in the CNS. These activated T cells release S-succinyl transferase (DLST) production [77]. Another
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 5 of 19

study found that during relapse, RRMS patients exhibited phospholipids (PLs) possess natural anti-inflammatory
increased extracellular acidification rate (ECAR) and oxy- properties, reducing EAE symptoms by inhibiting the
gen consumption rate (OCR), which were not observed activation of autoreactive ­C D4+ T cells and promoting
during the remission when compared to the healthy con- apoptosis. This effect is achieved through the suppres-
trols. Teriflunomide treatment could prevent the prolifer- sion of Bcl-2-interacting molecule Bim and Bad phos-
ation of metabolically active high-affinity T cells involved phorylation [90]. Deletion of acetyl-CoA carboxylase
in the progression of RRMS patients during relapse. This 1 (ACC1) in C ­ D4+ T cells prevents de novo fatty acid
effect is associated with a functional downregulation of production, inhibits the glycolytic-lipogenic pathway,
OCR and ECAR, along with complex III activity of the and protects mice from EAE by reducing the number
ETC in activated T cells. However, it has no impact on of IFN-γ+ Th17 cells and increasing the number of
mitochondrial content or structure [78]. ­FOXP3+ Tregs in the spinal cord [91]. Atorvastatin,
an inhibitor of HMG CoA, inhibits lipid metabolism
Mitochondria in MS ­CD4+ T cells
and suppresses the T cell activation and differentiation
A study revealed decreased Fas-mediated apoptosis of of Th1 and Th2 cells. This immune regulation can be
­CD4+ ­CCR5+ T cells in PPMS patients [79]. Moreover, reversed by using HMG CoA reductase L-mevalonate
activated ­CD4+ T cells in patients with RRMS exhibited [92]. These findings offer valuable insights into how
increased expression of the GLUT1 protein at the plasma lipid metabolism regulates the delicate balance between
membrane. This upregulation facilitated the uptake of tolerance and adverse immune responses [93].
glucose, leading to significant glucose metabolism and Inhibitors of 6-phosphofructo-2-kinase/fructose-
subsequent lactate production. Oxidative stress may be 2,6-biphosphatase 3 (PFKFB3), which indirectly reduce
associated with this process, as it lowers the protective hypoxia-inducible factor 1α (HIF-1α) activation, have
enzymes superoxide dismutase (SOD) and glutathione been shown to inhibit Th17 differentiation and exert
peroxidase (GPX), while raising the expression of the beneficial effects on MS patients by regulating glycoly-
protein Hsp70 [75]. Consistently, high glucose intake sis as the main regulator [94]. Upregulated ATP-linked
exacerbates autoimmunity in EAE and promotes the dif- OXPHOS in naïve C ­ D4+ T cells can promote Th17 cell
ferentiation of Th17 cells through ROS-driven activation differentiation in EAE/MS through decreased expres-
of transforming growth factor (TGF)-β signaling in ­CD4+ sion of aids basic leucine zipper transcription factor
T cells. However, there were no changes observed in TF-like (BATF). Otherwise, this state will switch to
mitochondrial OCR and ECAR in C ­ D4+ T cell metabo- Treg differentiation [95]. Consistently, mice lacking
lism [80]. Tregs with a prominent ROS signature in EAE BATF exhibited resistance to EAE due to increased
mice were found. Inhibiting ROS with MitoTEMPO in chromatin accessibility of Th17 transcription factors
Tregs of EAE mice attenuated the DNA damage response, [96]. The upregulation of mitochondrial elongation fac-
prevented Treg cell death, and reduced the differentiation tor G1 (mEF-G1) is implicated in the mitochondrial
of Th1 and Th17 cells [81]. Other findings also indicate translation process, leading to enhanced ETC assembly
that increased ROS during pathogenic Th1 and Th17 cell and an increased intracellular ratio of ­NAD+/NADH in
development could be a potential metabolic target for ­C D4+ T cells. This upregulation subsequently promotes
MS [82]. the development of Th17 and Th1 cells in MS/EAE.
There were significant differences in lipid species The observed phenotypes showed potential for rever-
­ D4+ T cells between MS patients and con-
specific to C sal with the administration of the antibiotic linezolid,
trol subjects [83]. Short-chain fatty acids (SCFAs) and which perturbing mitochondrial translation in differ-
long-chain fatty acids (LCFAs) were shown to be cru- entiating T cells [97]. Defective cellular metabolism,
­ D4+ T cells during the
cial for the differentiation of C including downregulation of ECAR and OCR, pre-
progression of EAE mice [84, 85]. Oleic acid, a type vents class III phosphatidylinositol 3-kinase (Pik3c3)-
of LCFA, restores suppressive deficiencies in tissue- deficient ­C D4+ T cells from differentiating into Th1
resident Tregs from MS patients by enhancing fatty cells and makes them resistant to EAE induction [98].
acid β-oxidation [86]. SCFAs, particularly pentanoate, Deletion of Nur77 enhances OCR and ECAR levels in
induce metabolic rewiring by increasing mammalian ­C D4+ T cells, resulting in Th1 and Th17 differentiation
target of rapamycin (mTOR) activity in C ­ D4+ effector and exacerbating EAE progression [99]. Suppression
T cells. This increase leads to higher acetyl-CoA levels, of ATPase activity [95] or the use of PFKFB3 inhibitor
glucose oxidation, IL-10 secretion, OCR, and suppres- [94] or 2-deoxy-glucose (2-DG) [87] to control ­C D4+
sion of IL-17A production. Ultimately SCFAs affect T cell glycolysis can similarly modify Th17/Treg dif-
the balance of Th17/Treg and ameliorate the progress ferentiation. Altogether, ­C D4+ T cells heavily rely on
of MS/EAE [87–89]. Saturated fatty acid side chain mitochondrial metabolism and dysfunctions for their
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 6 of 19

Fig. 2 Mitochondria in MS ­CD4+ T cells. C ­ D4+ 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 N ­ AD+/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

differentiation in MS disease. The summarized mito- A higher mitochondrial mass and MMP have been found
chondrial metabolism scheme of MS ­C D4+ T cells is in the C­ D8+ T cell subset of RRMS patients, accompa-
depicted in Fig. 2. nied by increased expression of GLUT1. Treatment
with 2-DG, a glucose analogue, leads to reduced activa-
Mitochondria in MS ­CD8+ T cells ­ D8+ T cell subsets in RRMS patients, as proved
tion of C
CD8+ T cells represent another important therapeutic by decreased expression of the early activation marker
target for MS [100]. Cytotoxic C ­ D8+ T cells have been CD69, reduced levels of the high-affinity IL-2 receptor
detected in MS plaques, CSF, and demyelinated axons CD25, and lower production of TNF α [103].
[100]. Lactate, a byproduct of glycolysis, accumulates The study demonstrates that dimethyl fumarate (DMF)
in the CSF of MS patients [101]. Several investigations significantly alters the metabolic profile of human ­CD4+
have demonstrated that shifts in the metabolic activi- and ­CD8+ T lymphocytes and limits caspase-mediated
­ D8+ T cells, including glycolysis and OXPHOS,
ties of C apoptosis to combat oxidative stress by reducing intracel-
have diverse regulatory effects on the activation, differ- lular glutathione (GSH) levels, which are ROS scavengers.
entiation, and functionality of these immune cells [102]. As a result, there is an increase in mitochondrial ROS,
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 7 of 19

MMP levels, and an improvement in Cytc, ultimately B cells serve as effective APCs expressing costimula-
resulting in a reduction in mitochondrial OCR [104]. tory molecules such as CD40, CD80, and CD86 as well
Another study has discovered that the inhibition of IL- as MHC class II [61, 106]. Compared to myeloid APCs,
17-producing ­CD8Mφ (Tc17) cells by DMF relies on ROS, they exhibit significantly higher efficiency, approximately
which is attributed to heightened PI3K-AKT-T-BET and 10,000 times, in capturing soluble and membrane-teth-
IL-2-STAT5 signaling pathways. Additionally, DMF-sign- ered antigens and presenting them to T cells [107]. In
aling is partially associated with the inhibition of type I or SPMS patients, mitochondrial damage has been observed
II histone deacetylases (HDACs) and histone acetylation around CNS periventricular ­CD20+ B cells [108].
on the IL-17 locus [105]. Enhancing our understanding In CSF memory B cells, single-cell RNA sequencing
of the role of mitochondria-targeted therapy in MS may studies have shown an increase in cholesterol produc-
offer a potential immunotherapeutic strategy to restrict T tion [109]. Obeticholic acid (OCA) is a unique medica-
cell-mediated autoimmunity in the future. Table 1 sum- tion that regulates various metabolic processes, including
marizes the mitochondrial and metabolic dysfunction cholesterol production, glucose metabolism, inflamma-
mechanisms that influence T cell function. tion, and apoptosis [110]. It has been proven the effec-
tiveness of OCA in treating EAE, reducing high-density
Mitochondria in MS B cells lipoprotein (HDL) levels, cholesterol, and the number of
B cells can be found in CNS lesions throughout all stages B cells, while OCA alleviates B cell exhaustion by reduc-
of MS, primarily localized to the perivascular cuffs. ing the expression of programmed cell death protein 1

Table 1 Mechanisms of mitochondrial and metabolic dysfunction that influence T cell function
Mechanism of mitochondrial and metabolic dysfunction T cell functions References

Bcl2, OPA1, PHB2, SIRT3, OMA1 and ATG5 regulate mitochondria- Regulate apoptosis of T cells [29, 68–72]
mediated death
Increase aldolase, HK-1, ENO1, GLUT1, DLAT and DLST, glycolysis Restore T cell metabolic remodeling [77]
and mitochondrial respiration activity via IFN beta treatment
Increase oxygen consumption rate (OCR) and extracellular acidifica‑ Prevent the proliferation of T cells [78]
tion rate (ECAR) through enhancing complex III activity of the ETC
after teriflunomide treatment
Reduction in the superoxide dismutase (SOD) and glutathione Regulate ­CD4+ T cell metabolic reprogramming [75]
peroxidase (GPX), as well as an increase in the protein Hsp70 caused
by oxidative stress, lead to increase GLUT1 and lactate
ROS-driven activation of TGF-β signaling in ­CD4+ T cells Encourage the differentiation of Th17 cells [80]
MitoTEMPO inhibits ROS in Treg Decline Th1 and Th17 cells differentiation [81]
Oleic acid enhances fatty acid β-oxidation of Treg Enhance inhibition of tissue-resident Treg [86]
Upregulated mTOR activity increases acetyl-CoA levels and glucose Increase IL-10 secretion and suppress IL-17A production in ­CD4+ T [87–89]
oxidation by pentanoate cells
Phospholipids (PLs) suppress phosphorylation of Bim and Bad Inhibit the activation and promotion apoptosis of autoreactive [90]
molecules ­CD4+ T cells
Acetyl-CoA carboxylase 1 (ACC1) promotes de novo fatty acid Increase IFN-γ+ Th17 cells number and decrease ­FOXP3+ Tregs [91]
production and the glycolytic-lipogenic pathway number in the spinal cord
Atorvastatin induces p-STAT6, inhibits p-STAT4 expression and cho‑ Promote Th2 cells differentiation, inhibit Th1 and Th 17 cells dif‑ [92]
lesterol synthesis ferentiation
Inhibit PFKFB3-HIF1α activation Decline Th17 cells differentiation [94]
Decrease transcription factor TF-like (BATF) expression and upregu‑ Promote Th17 cells differentiation and increase the chromatin [95, 96]
late ATP-linked oxidative phosphorylation (OXPHOS) accessibility
Linezolid disrupts the integrity of the ETC by inhibiting mitochon‑ Promote Th17 and Th1 cells differentiation [97]
drial elongation factor G1 (mEF-G1) and the ratio of ­NAD+/NADH
Pik3c3-deficient ­CD4+ T downregulation of ECAR and OCR Inhibit Th1 cells differentiation [98]
Nur77 knock-out enhances OCR and EACR​ Promote Th1 and Th17 cells differentiation [99]
2-DG treatment in ­CD8+ T cells reduces CD69 and CD25 Decrease ­CD8+ T cells activation and TNF α production [103]
DMF reduces intracellular GSH, CytC and induces ROS, mitochon‑ Increase apoptosis of ­CD4+ T cells and ­CD8+ T cells [104]
drial membrane potential (MMP), OCR and caspase-mediated
apoptosis
DMF increases ROS in Tc17 cells through PI3K-AKT-T-BET and IL- Decrease IL-17 production in Tc17 cells and inhibit type I or II his‑ [105]
2-STAT5 signaling pathways tone deacetylases (HDACs) histone acetylation on the Il17 locus
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 8 of 19

(PD1) and programmed death ligand 1 (PD-L1) [111]. The small molecule inhibitor 6877002 targeting the
Evidence suggests that increased levels of glycolytic CD40-TRAF6 pathway alters human inflammatory
enzymes, glyceraldehyde 3-phosphate dehydrogenase monocytes, resulting in reduced production of ROS,
(GAPDH), and triosephosphate isomerase (TPI), in the TNF, and IL-6, while increasing the production of IL-10.
CSF may contribute to B cell clonal growth in the CNS of This treatment also enhances the ability of monocytes to
MS patients [112]. reduce trans-endothelial migration, which is significant
In vitro studies have demonstrated that inhibition of when monocytes infiltrate the CNS during neuroinflam-
mitochondrial respiration decreases B cell activation (but mation in EAE [115]. Lactate dehydrogenase (LDH), con-
not glycolysis). On the other hand, both mitochondrial sisting of lactate dehydrogenase A (LDHA) and LDHB
respiration and glycolysis are involved in B cell prolifera- subunits, is a crucial enzyme in the anaerobic glycolysis
tion, with a notably higher dependence on mitochondrial metabolic pathway implicated in MS pathology [116].
respiration. Additionally, the expression of costimula- LDHB favors the conversion of lactate to pyruvate, while
tory molecules CD80 and CD86 is reliant on mitochon- LDHA, as a rate-limiting enzyme, has a higher affinity
drial respiration rather than glycolysis. The dysregulated for pyruvate, converting it into lactate [117]. Remarkably
activation and upregulation of CD80 and CD86 on B higher levels of LDHA on C ­ D11b+ monocytes in blood
lymphocytes from untreated individuals with MS can be from EAE mice have been observed compared to the
effectively counteracted by inhibiting Bruton’s tyrosine control condition [118].
kinase (BTKi) as well as modifying metabolic processes. Monocytes derived from EAE mice treated with 2-DG
Furthermore, BTKi therapy reduces OCR in circulating display decreased glucose uptake and reduced lactate
B cells, attenuates their activation and antigen present- production in the surrounding medium. Additionally,
ing potential in vivo, partially through the PI3K/AKT/ these monocytes exhibited decreased ECAR, which cor-
mTOR pathway [113]. Taken together, these findings related with a decrease in the expression of key glycolytic
indicate that glycolysis, cholesterol metabolism, and enzymes including Glut1, HK-2, TPI, pyruvate kinase M
mitochondrial respiration play crucial roles in regulating (PKM), LDHA, and monocarboxylate transporter (MCT)
B cell functions associated with the pathophysiology of 1. Monocytes treated with 2-DG adopted an immune-
MS. Table 2 provides a summary of the effects of mito- modulatory phenotype, and once them transplanted into
chondrial and metabolic dysfunction pathways on B cell EAE mice, resulted in a significant improvement in dis-
activities. ease severity [114]. These findings indicate that glycolysis
is highly upregulated in activated monocytes in MS.
Mitochondria in MS monocytes Comparison between the MS group and the control
Monocytes, a type of immune cell, have been shown to group revealed that monocytes treated with MS-CSF
influence mitochondrial function in patients with MS. produced more pyruvate and glutamine. Extracellular
They play a significant role in the demyelination pro- levels of glutamine, lactate, and pyruvate were signifi-
cess observed both in MS and EAE and they exhibit high cantly increased, while levels of glutamic acid were sig-
adaptability. Once they infiltrate the CNS during dis- nificantly decreased [119]. Quantification of monocyte
ease progression, monocytes can differentiate into either numbers and assessment of monocytic ROS levels
inflammatory or immune-modulatory macrophages, revealed an upregulated trend following DMF adminis-
depending on local conditions. The ratio of these mac- tration, allowing for the distinction between responders
rophage types ultimately determines the course of MS and non-responders. Mechanistically, a single nucleotide
[114]. Functional enrichment analysis using GWAS data- polymorphism (SNP) in NOX3 (rs6919626 A) is associ-
sets revealed a strong association among unique risk ated with ROS production and responsiveness to DMF
genes in monocytes and mitochondria and lipid metabo- treatment [120]. Mitochondrial dysfunction pathways
lism [11]. were upregulated in monocytes of individuals who did

Table 2 The impact of mitochondrial and metabolic dysfunction on B cell functioning

Mechanism of mitochondrial and metabolic dysfunction B cell functions References

Downregulated high-density lipoprotein (HDL) production by obeticholic acid (OCA) treatment Reduce the number of B cells [111]
and B cell exhaustion
Upregulated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and trisaccharide phosphoi‑ Drive B cell clonal expansion [112]
somerase (TPI) in the CSF
BTKi treatment limits OCR in B cells partially through PI3K/AKT/mTOR pathway Attenuate B cell activation [113]
and antigen-presenting function
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 9 of 19

not respond to IFN-beta treatment. Monocytic ROS compared to non-responders [121, 122]. These results
production slightly decreased, and several mitochon- suggest that mitochondrial translation, oxidative stress,
drial ETC-related genes showed significant alterations and intracellular glycolysis are crucial for monocyte
in monocytes that responded to IFN-beta treatment function and pathology, particularly in the context of

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

Table 3 Mechanisms of mitochondrial and metabolic dysfunction that affect monocyte functions
Mechanism of mitochondrial and metabolic dysfunction Monocytes functions References

The inhibitor 6877002 decreases ROS production of monocytes Reduce pro-inflammatory cytokines (TNF, IL-6) production [115]
through CD40-TRAF6 pathway and trans-endothelial migration ability
2-DG treatment reduces glucose uptake, lactate secretion and ECAR Switch to an anti-inflammatory phenotype and 2-DG treated [114]
in monocytes, which was correlated with a decrease in the expres‑ monocytes attenuate the severity of experimental autoimmune
sion of Glut1, HK-2, TPI, PKM, LDHA, and MCT-1 encephalomyelitis (EAE)
DMF treatment increases ROS production in monocytes, which Increase the numbers of monocytes [120]
was correlated with genetic variation and CpG methylation
in monocytic NOX3
IFN-beta treatment alters mitochondrial dysfunction pathway Decrease monocytic ROS production [121, 122]
and mitochondrial ETC-related genes
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 10 of 19

mitochondrial therapy drugs (Fig. 3). Table 3 provides a injury mediated by free radicals in the pathogenesis of
summary of the pathways involving mitochondrial and MS.
metabolic disorders that impact monocyte activities. MCTs play a crucial role in exporting lactate in gly-
colytic cells [137]. MCT-4 and LDHA are upregulated
in inflammatory Mφ of postcapillary venules in MS
Mitochondria in MS Mφ patients. Knockdown of LDHA or MCT-4 significantly
Mφ actively participate in the immune response to reduces lactate levels in macrophage supernatant after
autoimmune diseases and have been implicated in the lipopolysaccharide (LPS) treatment. Additionally, the
destruction of myelin and axons in MS lesions [123]. MCT-4 inhibitor α-cyano-4-hydroxy-cinnamic acid
Immunoregulatory Mφ (M2) drive the remyelination (CHCA) effectively decreases lactate levels and pre-
of damaged axons, produce neurotrophic factors, and vents inflammatory activity in Mφ. The LDHA inhibitor
facilitate oligodendrocyte function [64]. DMF efficiently 3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaph-
inhibits antigen-presenting function in Mφ, suppress- thalene-1-carboxylic acid (FX11) also exhibits lactate-
ing pro-inflammatory mediators such as ROS, induc- reducing properties in Mφ, inhibiting their inflammatory
ible NO synthase (iNOS), TNF-α, IL-1β, and IL-6. DMF function [118]. Another study shows that enhanced gly-
achieves this by decreasing extracellular signal-regulated colysis in infiltrating MHC-II+ Mφ leads to increased
kinase (ERK) phosphorylation, promoting M2-like Mφ expression of glucose transporters (GLUTs) such as
in an EAE mouse model [124]. Furthermore, it has been GLUT1, GLUT3, GLUT4, and MCT1, actively contrib-
demonstrated that DMF significantly blocks glycoly- uting to demyelination in MS lesion tissue [138]. These
sis by inhibiting GAPDH in murine Mφ [125]. This may findings indicate that elevated glycolysis is partially asso-
help explain how DMF promotes M2-like Mφ, consider- ciated with increased expression of glycolytic kinase pro-
ing that M1 Mφ primarily utilize glycolysis while M2 Mφ teins, which are integral to inflammatory macrophage
exhibit greater OXPHOS activity [125, 126]. Moreover, activation and contribute to demyelination in MS lesions
FhHDM-1, a 68-mer peptide secreted by the helminth (Fig. 4). The impact of mitochondrial and metabolic dys-
parasite Fasciola hepatica, inhibits the progression of function mechanisms on Mφ functions is summarized in
EAE/MS by upregulating OXPHOS and decreasing gly- Table 4.
colysis in Mφ. This leads to the inhibition of Mφ activa-
tion and production of pro-inflammatory cytokines, such Mitochondria in MS neutrophils
as TNF and IL-6 [127, 128]. Neutrophils, a crucial population of granulocytes, play
ROS are rapidly produced in the CNS of MS patients, a key role in initiating inflammatory responses [139].
predominantly by activated Mφ responsible for demyeli- Neutrophils in MS display an activated phenotype char-
nation and disruption of axons [129, 130]. These oxida- acterized by increased surface expression of TLR-2 and
tive bursts in Mφ contribute to focal axonal degeneration, N-formyl-methionyl-leucyl-phenylalanine receptors
which is further exacerbated by mitochondrial damage (fMLPR). Additionally, their adhesion and migration
and iron release from MS lesions [131, 132]. The p47phox energies are increased [140]. Once neutrophils enter
subunit of nicotinamide adenine dinucleotide phosphate the target site and become activated, they exhibit vari-
(NADPH) oxidase, primarily localized within the zone of ous effector functions aiming at neutralizing the entry of
initial damage or lesions in patients with acute or early pathogens. These effector activities include phagocytosis,
RRMS, accumulates in infiltrating Mφ and mediates degranulation, and the secretion of ROS.
ROS generation [133, 134]. RNA sequencing analysis The abundance and function of mitochondria in neu-
reveals that fibrin induces the core oxidative stress signa- trophils have been discussed for a long time. It is believed
ture (including neutrophil cytosolic factor (Ncf ) 2, Sod2, that instead of involved in ATP synthesis primarily, neu-
and Nox2) and the p47phox subunit of NADPH oxidase trophil mitochondria appear to have diverse functions
expressed by R ­ OS+ Mφ [135, 136]. In an EAE mouse including mtDNA copy number and mitochondrial
model, the transcriptomic signature of fibrin indicates a potential [141]. Moreover, a study found no significant
decrease in oxidative stress, demyelination, axonal harm, differences in intracellular ROS generation between
and prevention of paralysis when mice are exposed to the RRMS patients and healthy controls [142]. However,
fibrin-targeting antibody 5B8. This evidence suggests that selective deletion of CXCR2 in neutrophils is crucial
fibrin plays a significant role in triggering gene programs for downregulating Ncf1. This downregulation leads to
associated with oxidative stress during the activation of the inhibition of ROS and IL-1β production in neutro-
peripheral Mφ in EAE [135]. Taken together, these find- phils, resulting in attenuated CNS neuronal damage in
ings suggest that the inflammation-associated oxida- EAE disease [143]. In case of lacking Socs3, neutrophils
tive burst in Mφ contributes to demyelination and tissue
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 11 of 19

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

Table 4 Mechanisms of mitochondrial and metabolic dysfunction influence Mφ functioning

Mechanism of mitochondrial and metabolic dysfunction Mφ functions References

DMF blocks the glycolysis process and ROS production by decreas‑ Inhibit antigen-presenting function in Mφ and switch to M2 [124, 125]
ing extracellular signal-regulated kinase (ERK) phosphorylation phenotype
FhHDM-1 upregulates oxidative phosphorylation (OXPHOS) Inhibit Mφ activation and pro-inflammatory cytokines expression [127, 128]
and decreases glycolysis
P47phox mediated ROS generation Accumulate in infiltrating Mφ and involved in demyelination [133, 134]
Fibrin upregulates ROS production through enhancing oxidative Promote activation of Mφ and demyelination and axonal damage [135, 136]
stress genes (Ncf2, Sod2, Nox2) and p47phox
Deleting LDHA or MCT4 reduces lactate production Inhibit pro-inflammatory Mφ activity [118]
Glycolysis upregulated in MHC-II+ Mφ was associated with glucose Promote MHC-II+ Mφ activity in demyelination [138]
transporters (GLUTs) and MCT-1
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 12 of 19

Table 5 Mechanisms of mitochondrial and metabolic dysfunction influencing neutrophil function

Mechanism of mitochondrial and metabolic dysfunction Neutrophils functions References

Knock-out CXCR2 reduces ROS production through inhibiting Ncf1 and IL-1β produc‑ Reduce the inflammatory cytokines [143]
tion
Deficiency of Socs3 elevates ROS through activating G-CSF/STAT3 signaling Enhance neutrophil activation [144]

demonstrated heightened activation of granulocyte phagocytosis (LAP). Deletion of NOX2 in DCs inhibits
colony-stimulating factor (G-CSF)/STAT3 signaling, the myelin peptide presentation of DCs, preventing the
resulting in atypical EAE characterized by intensified recruitment of C ­ D4+ cells to the CNS in EAE mice [154].
neutrophil activation and elevated generation of ROS Activation of HIF-1α by lactate induces NDUFA4L2 and
[144]. The impact of mitochondrial and metabolic dys- limits the pro-inflammatory activities and activation of
function pathways on neutrophil activities is summarized DCs. The inhibition of transcription factor X-box binding
in Table 5. protein 1 (XBP1) by NDUFA4L2 in DCs plays a crucial
role in controlling pathogenic autoimmune T cells in EAE
Mitochondria in MS DCs mice. This regulatory mechanism is achieved through the
DCs, a type of APCs, are divided into conventional DCs downregulation of oxidative phosphorylation reprogram-
(cDCs) and plasmacytoid DCs (pDCs) [145]. pDCs pro- ming and ROS production [155].
duce a large amount of type I IFN, which plays a role Loss of responsiveness to TGF-β receptor II (TGF-
in antiviral innate immunity and exists in the blood as βRII) in monocyte-derived DCs (moDCs) results in
immature cells [146]. The number of cDCs and pDCs is increased secretion of IL-12 by moDCs, inducing polari-
significantly upregulated in the CSF of MS patients [147, zation toward an interferon-gamma-producing Th1 phe-
148]. In EAE, pDCs promote Tregs expansion and inhibit notype and exacerbating EAE disease. Mechanistically,
the development of ­CD4+ T cells into Th1 and Th17 cells upregulated IFN-γ increases Nox-2 and ROS production
[149, 150]. Interferon beta-treated DCs induce the gene in moDCs during chronic EAE [156]. DMF induces type
expression of IL-12p35 and IL-27p28, which suppress the II DCs by reducing intracellular GSH through the forma-
differentiation of Th17 cells and induce IL-10 secretion tion of conjugates, leading to upregulation of heme oxy-
through the activation of STAT1 and STAT3 in MS [151]. genase-1 (HO-1) levels [157]. GSH acts as an effective
Research highlights the importance of sirtuin 6 (SIRT6) scavenger of ROS, while HO-1 is a sensitive heat shock
in regulating several processes such as DNA repair, protein that may result in higher ROS production [158,
inflammation, immunology, and energy metabolism, 159]. Additionally, DMF prevents DCs from expressing
including glucose and lipid metabolism [152]. Inhibition pro-inflammatory cytokines and costimulatory molecules
of SIRT6 attenuates the onset of EAE by reducing DC [160, 161]. In part, the modulation of the GSH-HO-1
migration and activation, potentially mediated via meta- pathway by DMF treatment regulates the oxidative stress
bolic pathways [153]. NADPH oxidase 2 (NOX2) plays a during DC maturation and antigen-presenting capac-
crucial role in regulating the endocytosis of MOG anti- ity. These findings suggest that targeting mitochondrial
gen processing in DCs and supports the presentation of activities of DCs holds promise for the treatment of MS.
MOG antigen to ­CD4+ T cells through LC3-associated Table 6 provides a comprehensive overview of the impact

Table 6 The impact of mitochondrial and metabolic malfunctioning pathways on the activities of DCs
Mechanism of mitochondrial and metabolic dysfunction DC functions References

Sirt6 inhibition potentially mediates metabolic pathways Reduce migration and activation of DCs [152, 153]
Knock-out NOX2 in DCs can inhibit T cell-mediated autoimmune Inhibit myelin peptide presentation of DCs [154]
neuroinflammation through LC3-associated phagocytosis (LAP)
Increased HIF-1α-NDUFA4L2 signaling inhibits X-box binding Promote pro-inflammatory activities and activation of DCs [155]
protein 1 (XBP1) and leads to downregulating OCR and ROS
Tgfbr2 insufficiency in moDCs upregulates ROS production Secret more IL-12 in moDCs which induces Th1 polarization [156]
via NOX2 and chronic inflammatory demyelination
DMF partly though GSH-HO-1 pathway regulating oxidative stress Decrease maturation and antigen‐presenting capacity of pro- [157, 160, 161]
inflammatory DCs
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 13 of 19

Table 7 The present study investigates the impact disease-modifying therapy (DMT) medications on several immune cell
populations, with a particular focus on the underlying processes including mitochondrial and metabolic dysfunction
DMT drugs Immune cell type Mechanism of mitochondrial and metabolic dysfunction References

Interferon beta T cell Reverse the decreased glycolysis and mitochondrial respiration activity by upregulat‑ [77]
ing the expression of aldolase, HK-1, ENO1, GLUT1, DLAT and DLST
DC Suppress the differentiation of Th17 cells and induces IL-10 secretion via activated [151]
STAT1 and STAT3
Monocyte Alter monocytic ROS production and mitochondrial ETC-related genes [121, 122]
Dimethyl fumarate (DMF) CD4 or CD8 Increase caspase-mediated apoptosis through CytC, reduce intracellular GSH, increase [104]
MMP, ROS levels and mitochondrial OCR
Tc17 Upregulate ROS in Tc17 cells through PI3K-AKT-T-BET and IL-2-STAT5 signaling path‑ [105]
ways
Monocyte Upregulate monocytic ROS production as a result of genetically sustained low level [120]
of the promotor methylation of NOX3
Mφ Inhibit glycolysis process and ROS production through decreasing ERK phosphoryla‑ [124]
tion
DC Regulate oxidative stress potentially through modulation GSH-HO-1 pathway [157, 160, 161]
Teriflunomide T cell Enhance OCR and EACR by boosting complex III activity in the ETC [78]

of mitochondrial and metabolic dysfunction pathways on MS. This intervention has a significant positive impact on
DC activities. the overall disease status, as summarized in Table 7.
However, the complex nature of pathophysiological
mechanisms underlying mitochondrial metabolism in
Conclusion MS poses challenges for disease diagnosis and treatment.
Metabolic processes such as glycolysis, the TCA cycle, Unfortunately, current research on precision medicines
and lipid metabolism have a strong connection with specifically targeting connections within mitochondrial
mitochondrial activities. Furthermore, there may exist metabolic pathways is deficient. Further investigation
a reciprocal link among immune metabolism, immune into the mitochondrial and metabolic abnormalities of
cell activation and mitochondrial function. Metabolic immune cells, utilizing multi-omics combination tech-
processes and activities play a significant role not only niques and high-dimensional single-cell analysis, may
in producing ATP and biosynthetic precursors but also enhance our understanding of the pathophysiology of
in influencing immunological responses and the func- MS.
tioning of mitochondria in immune cells. However, it
is still unclear whether the improvement in abnormal
Abbreviations
metabolism is primarily caused by the reprogramming of MS Multiple sclerosis
immune activation or mitochondria. RRMS Relapsing–remitting
Research has primarily focused on investigating altera- SPMS Secondary progressive
PPMS Primary progressive
tions in the morphology, organization, and functionality MRI Magnetic resonance imaging
of mitochondria in immune cells affected by MS. These CNS Central nervous system
investigations have explored various mitochondrial meta- CSF Cerebrospinal fluid
GWAS Genome-wide association studies
bolic activities, including mitochondrial respiration, ROS APCs Antigen-presenting cells
production, MMP, TCA metabolic enzymes, and metab- EBV Epstein–Barr virus
olites. Mitochondrial dysfunction manifests with varying ATP Adenosine triphosphate
ETC Electron transport chain
severity across different immune cell populations at dif- ROS Reactive oxygen species
ferent stages of MS progression. Furthermore, the pres- TCA​ Tricarboxylic acid
ence of abnormal metabolites influences the functionality mtDNA Mitochondrial DNA
OXPHOS Oxidative phosphorylation
and maturation of cellular mitochondria, leading to the DMTs Disease-modifying therapies
persistent release of pro-inflammatory cytokines, neu- BBB Blood–brain barrier
rodegeneration, and demyelination, ultimately affecting EAE Experimental autoimmune encephalomyelitis
MOG Myelin oligodendrocyte glycoprotein
the progression of MS. Several DMTs targeting mito- PLP Proteolipid protein
chondria and metabolites have been shown to enhance MBP Myelin basic protein
the metabolic activity of immune cells in individuals with NO Nitric oxide
Wang et al. Journal of Neuroinflammation (2024) 21:28 Page 14 of 19

TLRs Toll-like receptors moDCs Monocyte-derived DCs

Treg Regulatory T cells HO-1 Heme oxygenase-1
LT Lymphotoxin
TNF Tumor necrosis factor Acknowledgements
MAIT Mucosal-associated invariant T No applicable.
Mφ Macrophages
NK Natural killer Author contributions
IL Interleukin PFW and ZLH wrote the manuscript and created the figures. FJ, QMZ, WFY,
IFN Interferon YZH, and QL participated in the literature review and data summary. ZLH
GM-CSF Granulocyte macrophage-colony stimulating factor was the guarantor and revised the manuscript. All authors reviewed the final
DCs Dendritic cells manuscript.
Bcl2 B cell lymphoma 2
OPA1 Ocular atrophy 1 Funding
PHB2 Prohibitin 2 This research was supported by the Natural Science Foundation of Hunan
SIRT3 Sirtuin-3 province (2023JJ10088 to Zhao-Lan Hu) and the National Natural Science
ATG5 Autophagy related 5 Foundation of China (81901231 and 82271379 to Zhao-Lan Hu).
MMP Mitochondrial membrane potential
HK-1 Hexokinase 1 Availability of data and materials
ENO1 Enolase 1 Not applicable.
GLUT1 Glucose transporter 1
DLAT Dihydrolipoamide-S-acetyl transferase
DLST Dihydrolipoamide-S-succinyl transferase Declarations
ECAR​ Extracellular acidification rate
OCR Oxygen consumption rate Ethics approval and consent to participate
SOD Superoxide dismutase Not applicable.
GPX Glutathione peroxidase
TGF Transforming growth factor Consent for publication
SCFAs Short-chain fatty acids Not applicable.
LCFAs Long-chain fatty acids
mTOR Mammalian target of rapamycin Competing interests
PLs Phospholipids The authors declare that they have no competing interests. Figures were cre‑
ACC1 Acetyl-CoA carboxylase 1 ated with [Link].
PFKFB3 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3
HIF-1α Hypoxia-inducible factor 1α
BATF Basic leucine zipper transcription factor TF-like Received: 9 November 2023 Accepted: 8 January 2024
mEF-G1 Mitochondrial elongation factor G1
Pik3c3 Class III phosphatidylinositol 3-kinase
2-DG 2-Deoxy-glucose
DMF Dimethyl fumarate
GSH Glutathione References
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