The central nervous system (CNS) is especially vulnerable to metabolic changes since it is believed to lack energy stores [33]. Moreover, although the brain constitutes a small portion of body weight, its daily energy consumption oscillates around 20%. Out of this energy expenditure, neurons take up the majority since they need a vast amount of energy for rapid axonal impulse conduction [73].

Glucose, the main energy substrate used by brain cells, is involved in many essential functions such as ATP production, synthesis of neurotransmitters, and oxidative stress management [74]. Brain cells generate ATP from glucose mainly by two metabolic pathways: glycolysis in the cytosol and oxidative phosphorylation (OX-PHOS) in the mitochondria. ATP obtained from OX-PHOS is obtained in combination with the production of NADH from the citric acid cycle (TCA) [75].

OLs preferentially use glycolysis over OX-PHOS to cover their high ATP demand [76]. Under favourable and nutrient rich conditions, human derived OPCs and OLs rely significantly more on glycolysis to generate ATP. However, when faced with stress or pathological conditions, oligodendrocytes have the ability to withdraw their processes from the myelin sheath, adopting a less metabolic state as a survival mechanism. Nonetheless, this retraction results in the destabilization of compact axonal myelin sheath. In contrast, OPCs fail to retract their processes and therefore quickly undergo cell death under stress [77].

The elevated glycolytic activity of OLs can result in the generation of pyruvate in the cytosol, which serves as metabolic support for neuronal oxidative metabolism. Nevertheless, mitochondria require more time to utilize the generated pyruvate, resulting in an excess of pyruvate. This surplus pyruvate is converted into lactate, which is the final product of glycolysis [78]. Lactate is then released into the periaxonal space through the monocarboxylate transporter 1 (MCT1) and subsequently taken up by axons through the neuronal MCT2. This pathway by which oligodendrocytes provide trophic support to the axons is known as the oligodendrocyte–axon lactate shuttle [79,80]. The elevated lactate production and transport can have a positive impact on the axons. The myelin wrapping these axons create specialized channels known as “myelinic channels”, which facilitate the transport of lactate and other beneficial factors to the axons, thereby promoting the maintenance and health of the axonal structures [81].

In addition to serving as metabolic fuel for oligodendrocytes, lactate can also be used by these cells for lipid production. In vitro experiments have demonstrated that lactate can enhance the mouse OPC differentiation process [82]. When faced with low glycose availability or hypoglycemic conditions, the proliferative and differentiating capacity of oligodendrocytes is diminished, as well as an inhibition in their ability to produce myelin is introduced [83]. Consequently, it could be concluded that the proper functioning of the oligodendrocyte and axon lactate exchange is essential for the differentiation of cells originating from the oligodendrocyte lineage [84].

However, in the presence of oxygen, OLs are particularly resistant to glucose withdrawal [85], revealing alternative mitochondria-dependent energy sources. Drosophila hold the capability to switch towards breaking down FAs in mitochondria when there is scarcity of carbohydrates. Experiments conducted on Drosophila subjected to long term nutritional stress conditions have shown that glial cells switch from glycolysis to β oxidation to provide axons with nutrients. In addition, glucose deprivation and β oxidation inhibition in oligodendrocytes induced rapid neurodegeneration [86]. The findings highlight that glial cells can rely on the degradation of glial fatty acids or peripheral lipid stores, which can be converted into ketone bodies, to sustain brain function and ensure survival in unfavourable conditions. Furthermore, this also suggests that ketone bodies could serve as alternative metabolic fuel for neurons [86,87].

Since the 1960s, it has been recognized that the two primary ketone bodies, acetoacetate and β-hydroxybutyrate, serve as metabolic fuels for the brain [88]. However, their potential to replace glucose in neuronal oxidative metabolism has only been uncovered recently [86]. The liver plays a central role in producing and storing ketone bodies, utilizing acetyl-CoA derived from imported fatty acids for ketogenesis [89]. However, it is believed that local lipid stores within the cortex glia of Drosophila have the ability to utilize their own reserves to generate ketone bodies and transport them to areas that are experiencing nutritional deprivation. Therefore, in times of starvation, these newly synthesized ketone bodies can be taken up by neurons and used as energy substrates to sustain memory formation [90].

For constant myelination to occur, there needs to be a constant synthesis of lipids which are supplied by oligodendrocytes. Lipid metabolites can also serve as energy reserves when facing low glucose conditions [91]. The autophagy-lysosomal pathway is responsible for recycling myelin lipids which results in the release of fatty acids that can be used to produce new myelin lipids [69]. However, when glucose availability is insufficient, OLs can redirect the fatty acids released during myelin breakdown towards β-oxidation resulting in acetyl-CoA production which acts as a substrate for OX-PHOS. Experiments conducted on a mouse optic nerve model have demonstrated that generating ATP from lipids allows for a greater allocation of glucose-derived metabolites to the axons, thereby supporting their preservation [78].

Peroxisomes, small organelles present in the cytosol of most eukaryotic cells, are also involved in a series of functions involving metabolism and detoxification of reactive oxygen species. Like mitochondria, they are essential for the β-oxidation of fatty acids, especially of very long chain fatty acids (VLCFA) [92] (Kassmann et al., 2007). Peroxisomes are abundant and can be spotted in numerous CNS cells, especially in glial cells. Recent studies have demonstrated the presence of peroxisomes within the innermost tongue of the myelin sheath [93,94]. The inhibition of peroxins, the proteins involved in the biosynthesis of these organelles, leads to their dysregulation and, consequently, to white matter abnormalities [95]. Thus, following these results, peroxisomes have been hypothesized to have a significant role in direct axonal support and myelin maintenance. Furthermore, peroxisomal inhibition studies have concluded that peroxisomes from myelin forming glia perform β-oxidation to chain shorten VLCFAs for their subsequent transfer into axonal mitochondria [94,96].

Several research studies employing various biological samples have now provided compelling evidence of abnormalities in the metabolome among individuals with MS [97,98,99,100]. Cerebrospinal fluid (CSF) samples of MS patients have revealed increased levels of lactate whilst also showing disturbances in glucose and energy metabolism. Studies using mass spectrometry-based metabolomics have shown alterations in lipid and fatty acid metabolism, with elevated concentrations of circulating free fatty acids and products of fatty acid oxidation being observed [101,102].

Two hypotheses have been proposed to explain the origin and pathological features of MS. The first one aims to explain that the cascade of events begins in the periphery where dysregulated auto-reactive T cells enter the CNS along with macrophages and B cells. This starts a target-directed attack on myelin sheaths, resulting in a RRMS course and CNS injury. Conversely, the second hypothesis states that MS is a neurodegenerative disease, with the initial malfunction or auto-inflammatory behaviour occurring within the CNS itself. In this hypothesis, chronic shedding of antigenic cell components occurs, leading to an inflammatory response and subsequent degeneration of the myelin sheath [21,102].

The second hypothesis, which proposes that MS is a neurodegenerative disease, finds support in the possibility of mitochondrial dysfunction. This dysfunction could lead to an energy deficiency and hinder various processes such as impulse transmission, axonal transport, and ion trafficking [103]. Evidence from an EAE study shows that this occurs before neurological dysfunction becomes apparent [104]. Furthermore, the impaired mitochondrial function not only leads to energy deficits but also triggers the activation of inflammatory cells within the CNS, further propelling the progression of neurodegeneration [105,106]. MS patients are characterized by reduced ATP production, potentially resulting from decreased activities of the mitochondrial electron transport chain complexes [107]. However, it is worth noting that in certain instances, complex V activity is sometimes enhanced as a compensatory mechanism for the lower activity of complex I. Despite this compensatory effort, the disruption in mitochondrial function ultimately results in decreased energy production [108].

Besides its involvement in altered bioenergetics, mitochondrial dysfunction is strongly associated with oxygen metabolism and the generation of Reactive Oxygen Species (ROS). As the brain utilizes a substantial proportion of inhaled air (20%) and consumes a significant amount of tissue oxygen (90%) for energy production, this metabolic process leads to the production of detrimental ROS [109]. ROS and their reactive products attack all classes of biomolecules, including lipids. Notably, the CNS, which comprises membranes with elevated levels of polyunsaturated fatty acids, renders neuronal cells highly sensitive and vulnerable to damage caused by the adverse effects of these reactive species. The consequence of the interaction between ROS and nitric oxide is the generation of highly reactive peroxynitrite [105]. This by-product specifically endangers OPCs due to their limited antioxidant defense mechanisms. As a result, OPCs are unable to undergo maturation into myelin-forming oligodendrocytes, leading to impaired myelin production and maintenance in the context of MS [110].

Mononuclear phagocytes (MPs) act as the CNS’s surveillance system, primarily responsible for local immune surveillance. The resident MPs include microglia, constituting approximately 5–10% of all brain cells, and macrophages residing in the perivascular spaces and choroid plexus [111]. Neurodegeneration results in a shift in the balance of microglial activation towards their pro-inflammatory state. This leads to the production of chemokines/cytokines, such as tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, and IL-12, which have pro-inflammatory properties [105].

Simultaneously, the secretion of these pro-inflammatory cytokines has adverse effects on crucial mitochondrial components, leading to a decline in mitochondrial respiratory chain function and exacerbating neurodegeneration [112]. Additionally, the enzymes responsible for the tricarboxylic acid cycle and oxidative phosphorylation within the mitochondria are adversely affected in the inflamed CNS due to the presence of these proinflammatory mediators [113]. Although the evidence suggests that inflammatory factors impact mitochondrial dynamics, the specific molecular mechanisms through which these mediators induce damage is still poorly understood.

Moreover, macrophages and microglia are recognized for their role in clearing myelin [23]. Nevertheless, during inflammatory conditions and when they adopt their pro-inflammatory state, they lose this capability, leading to increased oxidative stress due to disrupted myelin clearance [114]. Myelin also serves as a crucial barrier against oxidative stress. However, in the context of multiple sclerosis (MS), the disruption of myelin clearance leads to the accumulation of damaged myelin, exposing nerve fibres to increased oxidative stress causing a breakdown in nerve signal transmission and leading to neurological symptoms characteristic of MS [115].

It is essential to comprehend the intricate relationship between inflammation and bioenergetics in MS to explore potential therapeutic approaches. By addressing mitochondrial dysfunction and metabolic changes in immune cells, novel treatment possibilities could emerge, leading to disease progression slowdown.

In MS, there is evidence of altered glucose metabolism, with reduced glucose uptake and utilization in certain regions of the brain. This metabolic dysfunction can impact the energy supply to neurons and other cells, potentially contributing to neurodegeneration. Glucose deprivation conditions are believed to have detrimental conditions on OPCs, resulting in fewer and thinner processes while oligodendrocytes tend to shift to a more glycolytic state for their survival [116].

Furthermore, the lactate levels in both the serum and CSF of MS patients vary depending on the clinical stage. During the early stages of the pathogenesis, lactate levels tend to be lower, but as the disease progresses, an increase in lactate expression can be observed. It can be concluded that there is an elevation in extra-mitochondrial glucose metabolism in MS patients, which could also be associated with impaired mitochondrial function [117]. Taking into account the aforementioned data, the fluctuations in lactate levels have the potential to serve as diagnostic criteria as they could indicate the progression of the disease [118].

Lipids play vital roles in the brain, participating in various processes, including neurogenesis, signal transduction, neuronal communication, membrane compartmentalization, and the modulation of gene expression. Because of their essential structural and physiological functions, any changes in lipid metabolism may indicate abnormal brain function [119]. Scientific evidence indicates that there is a modification in the lipid metabolism of the arachidonic acid pathway, which undergoes changes in the context of multiple sclerosis pathology [120]. Furthermore, specific lipid abnormalities have been reported, such as deficiencies in FA 18:2 and FA 20:4, as well as total PUFA (polyunsaturated fatty acids), accompanied by compensatory increases in saturated fatty acids with shorter carbon chains [121].

Utilizing the untargeted lipidomics approach, studies have revealed distinctive lipid signatures in multiple sclerosis (MS) patients compared to healthy controls. MS patients exhibit a unique phospholipidomic profile, characterized by significant reductions in key phospholipids, including phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, which play crucial roles in antioxidant functions. Therefore, certain phospholipids hold promise as potential biomarkers for clinical applications in the context of multiple sclerosis (MS) [122,123,124].

Macroautophagy and lysosome-mediated degradation are essential processes that contribute significantly to myelin turnover and regeneration. Nevertheless, pathological and aging conditions frequently lead to a decline in the efficacy of these mechanisms. Consequently, this disruption negatively impacts the overall well-being of oligodendrocytes, impairing their ability to synthesize fatty acids crucial for myelin maintenance and energy production [69].

In addition, sphingolipids, important components of lipid bilayers with functional and structural roles, have been implicated in MS disease processes [125]. Recent research highlights alterations in sphingolipid pathways that could contribute to oligodendrocyte injury, suggesting dysregulated anti-inflammatory and pro-inflammatory lipids as potential contributors to MS pathology. Ceramide lipids, such as sphingosine, is associated with oligodendrocyte damage and acute demyelination [126]. Ceramide release from stressed oligodendrocytes could trigger autoimmune responses following active demyelination, potentially serving as a diagnostic and prognostic marker [127].

Studies also link cholesterol derivatives, known as oxysterols, to inflammatory demyelination in MS. With about 25% of the brain consisting of cholesterol, higher than in other organs, oxysterols, particularly 24(S)-hydroxycholesterol, can impact CNS cells due to disrupted BBB [128,129]. Oxysterols influence lipid synthesis by affecting transcription factors, such as sterol regulatory element-binding proteins (SREBPs), which regulate genes involved in lipid homeostasis [127].

Additionally, dysregulations in lipid metabolism can profoundly affect the stability and integrity of the myelin sheath due to a disruption in the interplay between lipid receptors and myelin proteins [130]. These molecular players orchestrate pivotal processes within the myelin sheath, including the intricate machinery driving its synthesis and restoration. By disturbing their functions, aberrant lipid metabolism could potentially impede the myelin sheath’s ability to maintain its structural integrity and engage in reparative activities [131]. Moreover, MBP, aside from its arrangement and behavior within the myelin sheath, also influences the organization of the lipid bilayer within myelin. Thus, alterations in MBP dynamics might thus reverberate throughout the lipid environment, potentially contributing to the overall stability and functionality of the myelin sheath [73,132].

All in all, considering the complex interplay of bioenergetics and lipid metabolism, the exact mechanisms underpinning these interactions remain complex and call for deeper investigation. More extensive research is crucial for unravelling whether the bioenergetics irregularities observed in MS specifically affect certain groups of lipids, as opposed to influencing the entire range. This would open possibilities to target specific lipid types whilst sparing others. Such findings could pave the way for targeted interventions aimed at specific lipid categories while leaving others unaffected.

Bioenergetics can significantly impact MS progression by impairing the function of the axon–myelin unit [133]. Indeed, disruption of the axon–myelin unit can occur acutely, such as during transient ischaemia, or chronically in MS and other neurodegenerative diseases, and involve myelinic NMDA receptors, a key component regulating the supply of energy substrates between oligodendrocyte/myelin and axons [134]. Thus, glutamate released by axons during action potential propagation activates NMDA receptors in oligodendrocytes that translocate glucose transporter GLUT1 into the plasma membrane, promotes glycolysis, and favours lactate shuttling to axons. This mechanism fine-tunes axonal energy demands during neuron-to-neuron communication, and it is impaired during dysmyelination and demyelination, leading to mitochondrial dysfunction and, eventually, to axonal damage. The detailed mechanisms would include: (i) energy failure due to the inability of oligodendrocytes to generate lactate for export to the axon, with a reduction on ATP synthesis in axonal mitochondria; (ii) an ensuing failure of ion transporters to maintain Na⁺ and K⁺ and therefore, impaired action potential propagation; and (iii) axonal Ca²⁺ dyshomeostasis causing enhanced activation of calpains, phospholipases, and other enzymes that ultimately result in structural axonal damage.

Accordingly, demyelinated axons in focal plaques in remitting-relapsing MS may undergo transient energy deficits compromising their function (signal transmission) and structure. Partial remyelination in shadow plaques may restore energy supply and prevent the fatal fate of compromised axons, but not in acute and chronic plaques without overt remyelination. Consequently, long-term bioenergetic deficits can lead to axon demise, anterograde and retrograde neuronal degeneration, and MS progression.