The Lactate–Mitokine Axis in Exercise Adaptation: Linking Glycolytic and Mitochondrial Stress Signaling
4 affiliations
- 1Biochemistry Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, Romania
- 2Pharmacognosy and Phytotherapy Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, Romania
- 3Pharmacology and Clinical Pharmacy Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, Romania
- 4Center for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, Romania
Abstract
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.
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BibTeX
@article{terovescan2026lactatemitokine,
title = {{The Lactate–Mitokine Axis in Exercise Adaptation: Linking Glycolytic and Mitochondrial Stress Signaling}},
author = {Amelia Tero-Vescan and Ruxandra Ștefănescu and Bianca Eugenia Ősz and Mădălina Buț and Amalia Pușcaș and Mark Slevin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219871},
url = {https://www.mdpi.com/1422-0067/27/21/9871},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Lactate–Mitokine Axis in Exercise Adaptation: Linking Glycolytic and Mitochondrial Stress Signaling
AU - Amelia Tero-Vescan
AU - Ruxandra Ștefănescu
AU - Bianca Eugenia Ősz
AU - Mădălina Buț
AU - Amalia Pușcaș
AU - Mark Slevin
PY - 2026
DA - 2026/11/04
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219871
UR - https://www.mdpi.com/1422-0067/27/21/9871
AB - 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.
SN - 1422-0067
ER -