The Lactate–Mitokine Axis in Exercise Adaptation: Linking Glycolytic and Mitochondrial Stress Signaling

Exercise induces coordinated metabolic and mitochondrial stress responses that extend beyond ATP production to regulate cellular and systemic adaptation. Lactate, traditionally viewed as a glycolytic product, is now recognized as an oxidative substrate, interorgan carbon shuttle, and signaling metabolite, whereas mitochondrial stress promotes adaptive signaling and the release of mitokines and mitochondrial-derived peptides. This narrative review proposes the lactate–mitokine axis as a conceptual framework integrating these two exercise-responsive systems, while distinguishing experimentally established mechanisms from potential interactions that remain to be functionally validated. Repeated exercise promotes mitochondrial remodeling and increases oxidative capacity, which in turn reshapes the lactate response to subsequent exercise, as reflected by lower post-exercise lactate concentrations and enhanced lactate clearance after training. Conversely, increased lactate flux may influence mitochondrial adaptation through metabolic, redox, and receptor-dependent signaling, supporting a potentially bidirectional relationship between lactate handling and mitochondrial remodeling. The relative contribution of these interconnected responses appears exercise modality-dependent, with high-intensity, prolonged endurance, and resistance exercise generating distinct combinations of glycolytic and mitochondrial stress. Although lactate metabolism and mitochondrial stress signaling share several regulatory pathways, direct causal interactions between lactate signaling and mitokine expression or secretion during exercise remain insufficiently established. Thus, the proposed lactate–mitokine axis should be regarded as a hypothesis-generating framework requiring further experimental validation.