From energy metabolism to mood regulation: The rise of lactate as a therapeutic target

Background: 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. Aim of review: 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. Key scientific concepts of the review: 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.