Lactate and lactylation modifications in neurological disorders

Abstract

Research into lactylation modifications across various target organs in both health and disease has gained significant attention. Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications. Lactate, once considered merely a byproduct of anaerobic metabolism, has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system. Furthermore, recent studies have emphasized the significant role of lactate in numerous neurological diseases, including Alzheimer's disease, Parkinson's disease, acute cerebral ischemic stroke, multiple sclerosis, Huntington's disease, and myasthenia gravis. The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases, aiming to clarify their mechanisms of action and identify potential therapeutic targets. As such, this work provides an overview of the metabolic regulatory roles of lactate in various disorders, emphasizing its involvement in the regulation of brain function. Additionally, the specific mechanisms of brain lactate metabolism are discussed, suggesting the unique roles of lactate in modulating brain function. As a critical aspect of lactate function, lactylation modifications, including both histone and non-histone lactylation, are explored, with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications, such as lactylation writers and erasers. The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized, revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders. Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.

Keywords: astrocyte-neuron lactate shuttle theory; brain functions; brain lactate metabolism; central nervous system; histone lysine lactylation; monocarboxylate transporters; nervous system; neurodegenerative diseases; non-histone lysine lactylation; post-translational modifications.