Mitochondrial Lactate Signaling and Protein Lactylation in Neurological Diseases

The brain, as a highly metabolically active organ, depends on mitochondrial oxidative phosphorylation (OXPHOS) to sustain energy demands. When mitochondrial function is impaired, cells undergo metabolic reprogramming toward aerobic glycolysis, leading to lactate accumulation. Beyond its traditional role as a metabolic byproduct, lactate is now recognized as a signaling molecule that links metabolism to epigenetic regulation through protein lactylation, a post-translational modification identified by Zhang et al. in 2019. Research on lactylation has progressed through three stages: initial discovery in histone lactylation as an epigenetic mark, expansion to non-histone proteins revealing roles in metabolic and structural regulation, and recent identification of mitochondrial protein lactylation influencing OXPHOS, the tricarboxylic acid (TCA) cycle, and reactive oxygen species (ROS) production. This review summarizes the mitochondrial-lactate-lactylation axis in the nervous system, including brain lactate metabolism, the astrocyte-neuron lactate shuttle, and regulatory mechanisms of lactylation (writers, erasers, and readers). We further discuss its roles in histone and non-histone modification, its bidirectional relationship with mitochondrial dysfunction, and its involvement in neurodegenerative, cerebrovascular, and neuropsychiatric disorders. Finally, we highlight the therapeutic potential of targeting lactylation pathways. Collectively, mitochondrial lactate signaling and protein lactylation emerge as a central link between metabolic reprogramming and epigenetic dysregulation in neurological diseases, providing new avenues for therapeutic intervention.