From energy metabolism to mood regulation: The rise of lactate as a therapeutic target
Sen Zhang, Jie Xia, Wenke He, Yong Zou, Wenbin Liu, Wenbin Liu, Lingxia Li, Zhuochun Huang, Qing X. Li, Zhengtang Qi, Weina Liu, Weina Liu
Abstract
• Cerebral lactate shuttling is a crucial pathway for neuronal energy metabolism and maintaining neuronal activity. • Cerebral lactate interacts with GPR81, SIRT1, and NMDAR to induce signaling cascades. • Stress-induced abnormalities in energy metabolism and lactate metabolism in the brain are involved in the pathology of mood disorders. • Cerebral lactate regulates neural development, neuroplasticity, blood–brain barrier maintenance, and lysosomal acidification, with potential implications for lactate-based interventions in mood disorders. • Exercise-induced fluctuations in brain lactate metabolism have the potential to ameliorate mood disorders. Disruption of cerebral energy metabolism is increasingly recognized as a key factor in the pathophysiology of mood disorders. Lactate, beyond its role as a metabolic byproduct, is now understood to be a critical player in brain energy homeostasis and a modulator of neuronal function. Recent advances in understanding lactate shuttling between astrocytes and neurons have opened new avenues for exploring its multifaceted roles in mood regulation. Exercise, known to modulate brain lactate levels, further underscores the potential of lactate as a therapeutic target in mood disorders. This review delves into the alterations in cerebral lactate associated with mood disorders, emphasizing their implications for brain energy dynamics and signaling pathways. Additionally, we discuss the therapeutic potential of lactate in mood disorders, particularly through its capacity to remodel cerebral function. We conclude by assessing the promise of exercise-induced lactate production as a novel strategy for mood disorder treatment. Alterations in brain lactate may contribute to the pathogenesis of mood disorders. In several studies, lactate is not only a substrate for brain energy metabolism, but also a molecule that triggers signaling cascades. Specifically, lactate is involved in the regulation of neurogenesis, neuroplasticity, endothelial cell function, and microglia lysosomal acidification, therefore improving mood disorders. Meanwhile, exercise as a low-risk intervention strategy can improve mood disorders through lactate regulation. Thus, the evidence from this review supports that lactate could be a potential therapeutic target for mood disorder, contributing to a deeper understanding of mood disorder pathogenesis and intervention.