Beyond Fuel: Metabolic Intermediates as Signaling Molecules in Neuroinflammation and Neurodegeneration

Abstract:

Historically, research has viewed substantial brain metabolic activity through the lens of energy production, primarily treating metabolites as substrates and products in bioenergetic pathways. However, this paradigm is now evolving. Key metabolic intermediates are recognized not only as components of Adenosine Triphosphate (ATP) synthesis, but also as potent signaling molecules that establish intricate communication networks. This "metabolic signaling language" profoundly influences inflammation, epigenetics, and cell fate by translating cellular metabolic conditions into certain functional outcomes. In this review, three prototypical metabolites, namely succinate, itaconate, and α-Ketoglutarate (α-KG), were discussed. We investigated succinate accumulation during ischemia and mitochondrial stress, which serves as an early alarm that drives inflammation through both intracellular and extracellular receptor-mediated mechanisms. Conversely, itaconate, an inducible metabolite produced by myeloid cells, exerts inhibitory effects and actively alleviates inflammation by covalently modifying proteins. Finally, we highlighted α-KG, a central metabolic hub that links metabolic status to cellular identity and aging by epigenetically regulating DNA and histone demethylase activity. By summarizing the functions of these metabolites across neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, we delineate a fundamental layer of biological regulation. Deciphering and therapeutic modulation of this metabolic language represent a frontier in neuroscience, offering novel targets for intractable neurological diseases.