Abstract

Many people living with multiple sclerosis (MS) experience aspects of normal aging years, or even decades, ahead of schedule. As their disease progresses, people with MS show reduced mobility and impaired cognitive functions, which all lead to a significant reduction of their activities of daily living. Sustained activation of resident and infiltrating myeloid cells is a common hallmark of several chronic neurological diseases, including MS. In MS, chronic active, slowly expanding, smoldering lesions are characterized by the accumulation of myeloid cells at the lesion edge and are associated with brain volume loss and progressive disability. Extensive metabolic rewiring occurs in cells in response to the local microenvironment as cells deal with shifting availability of energetic substrates and signalling molecules that ultimately modify their effector functions. However, the role of myeloid cell metabolism in driving persistent central nervous system inflammation in MS and other neurodegenerative diseases has not been fully elucidated yet. Using a complementary multiomics approaches, we identified a new molecular signature that sustains the persistent activation of microglia dependent on altered mitochondrial complexes activity driving the production of reactive oxygen species. We showed that specific TCA cycle metabolites (e.g., succinate) and lipid species accumulate in chronic central nervous system inflammation and modulate myeloid function, as well as key neuroimmune interactions. Finally, we showed that it is possible to correct the mitochondrial dysfunction of myeloid cells by using small molecules and acellular approaches, including mitochondria delivery via extracellular vesicles. Our work is shedding new light on the role of mitochondrial metabolism in guiding complex cellular functions in chronic central nervous system inflammation.

Dr. Luca Peruzzotti-Jametti is a Senior Research Associate (Wellcome Trust CRCD Fellow) and Honorary Neurology Consultant at the Department of Clinical Neurosciences.

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