Targeting Mitochondrial Metabolism in Neuroinflammation: Towards a Therapy for Progressive Multiple Sclerosis

MPs, including resident microglia and blood-borne macrophages, control local immune surveillance in the CNS. In chronic neurological conditions, such as MS, MPs are persistently activated and responsible for several maladaptive responses that include neurotoxicity and inhibition of remyelination. Cell metabolism guides the activation of MPs towards a proinflammatory or anti-inflammatory phenotype and function, depending on the local microenvironment. Specific metabolites act as intracellular and extracellular signalling molecules regulating neuroimmune interactions and inflammation. Neural stem cells interfere with MP metabolism via selective uptake of specific metabolites and secretion of metabolic enzymes packed into extracellular vesicles. The lack of effective treatment options for chronic neurological conditions, such as multiple sclerosis (MS), highlights the need to re-evaluate disease pathophysiology in the process of identifying novel therapeutic targets. The persistent activation of mononuclear phagocytes (MPs) is one of the major drivers of neurodegeneration and it sustains central nervous system (CNS) damage. Mitochondrial metabolism influences the activity of MPs, and the metabolites that they produce have key signalling roles in inflammation. However, how changes in immune cell metabolism sustain a chronic state of neuroinflammation is not fully understood. Novel molecular and cellular therapies for chronic neuroinflammation should be developed to target mitochondrial metabolism in innate immune cells to prevent secondary neurological damage and the accumulation of irreversible disability in patients. The lack of effective treatment options for chronic neurological conditions, such as multiple sclerosis (MS), highlights the need to re-evaluate disease pathophysiology in the process of identifying novel therapeutic targets. The persistent activation of mononuclear phagocytes (MPs) is one of the major drivers of neurodegeneration and it sustains central nervous system (CNS) damage. Mitochondrial metabolism influences the activity of MPs, and the metabolites that they produce have key signalling roles in inflammation. However, how changes in immune cell metabolism sustain a chronic state of neuroinflammation is not fully understood. Novel molecular and cellular therapies for chronic neuroinflammation should be developed to target mitochondrial metabolism in innate immune cells to prevent secondary neurological damage and the accumulation of irreversible disability in patients. comprises five complexes and two mobile electron carriers embedded in the mitochondrial membrane that link oxidation of carbon substrates to ATP production. The ETC couples the energy of electron transfer (from NADH and FADH2) to the generation of a proton-motive force across the inner membrane, which is used by complex V to drive ATP synthesis. electrophiles are ubiquitous reagents in aerobic organisms; they are attracted to electrons and arise from both xenobiotic challenge and internal metabolism. Although some electrophiles have physiological functions, many can trigger cell damage because of their reactive chemistry. Most species have evolved elaborate intrinsic strategies to cope with electrophilic stress. Genes encoding many of these defensive products contain an electrophile response element/antioxidant response element (EpRE/ARE) and are regulated by the transcription factor Nrf2, the activity of which is determined by the state of its redox-sensitive inhibitor Keap1. a murine model of MS that is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naïve recipients. Despite all the limitations of this model, it is still widely used to answer many of the immunological-oriented questions in MS research. the catabolic process by which FA molecules are broken down in the mitochondria to generate acetyl-CoA, which enters the TCA cycle, and NADH and FADH2, which are co-enzymes used in the ETC. the creation of FAs from acetyl-CoA and NADPH through the action of enzymes, fatty acid synthases, in the cytoplasm of the cell. the process by which glucose is incompletely oxidised in the cytosol, yielding lactate as its final product. Compared with oxidative metabolism, glycolysis is fast but energy inefficient. a network of lymphatic vessels located parallel to the dural sinuses and meningeal arteries in the mammalian CNS. Although its role in health and disease is yet to be fully characterised, a dysfunction of the meningeal lymphatic system might be relevant for diseases of the CNS, such as MS. part of the innate immune system, which comprises phagocytic cells either resident within tissues (e.g., microglia in the CNS) or blood-borne (e.g., macrophages). the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide. MS is currently incurable. macroscopically intact regions on conventional MRI that show a degree of chronic injury (e.g., axonal spheroids, microglial activation, gliosis, and increased expression of proteolytic enzymes) on deeper pathological characterisation. a shunt of glycolysis that produces NADPH, important for maintaining cellular redox balance and nucleotides. the dense accumulation of immune cells around blood vessels seen during inflammatory and/or immune reactions. characterised by the progressive accumulation of disability without identifiable acute relapses. Progressive MS includes secondary progressive (SP), which is the consequence of RR MS, and primary progressive (PP) MS, in which progression is present from the onset of the disease. characterised by discrete episodes of acute neurological deficits and/or worsening of a given neurological function (i.e., relapse), followed by a complete or partial recovery (i.e., remission). RR MS is the most common phenotype of MS (∼85% of total cases) and is the typical presentation of disease at onset. this process consumes proton motive force to drive electrons in a reverse direction through the ETC. RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of reactive oxygen species (ROS). white matter slowly expanding smouldering plaques in MS are characterised by an inactive centre with few macrophages, surrounded by a rim of activated microglia. Smouldering plaques occur almost exclusively in patients with progressive MS. a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA in the form of ATP. In addition, the cycle provides precursors for amino acids as well as the reducing agent NADH.