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Research Project: Impact of Maternal Influence and Early Dietary Factors on Child Growth, Development, and Metabolic Health

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Title: Myoglobin interaction with lactate rapidly releases oxygen: Studies on binding thermodynamics, spectroscopic and oxygen kinetics

item ADEPU, KIRAN KUMAR - Arkansas Children'S Nutrition Research Center (ACNC)
item BHANDARI, DIPENDRA - Arkansas Children'S Nutrition Research Center (ACNC)
item ANISHKIN, ANDRIY - University Of Maryland
item ADAMS, SEAN - University Of California, Davis
item CHINTAPALLI, SREE - University Of California, Davis

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/24/2022
Publication Date: 4/26/2022
Citation: Adepu, K., Bhandari, D., Anishkin, A., Adams, S.H., Chintapalli, S.V. 2022. Myoglobin interaction with lactate rapidly releases oxygen: Studies on binding thermodynamics, spectroscopic and oxygen kinetics. International Journal of Molecular Sciences.

Interpretive Summary: Traditionally and in every textbook, the muscle-abundant protein myoglobin (Mb) is viewed as an important contributor toward O2 sequestration and delivery to mitochondria in support of oxidative phosphorylation of fuels. Certainly, Mb releases O2 rapidly in response to a reduction in tissue O2 levels (i.e., drop in partial pressure [pO2]), as might be seen with an acute bout of exercise or in ischemia. Yet, several models of Mb knockout mouse models have not demonstrated that Mb is critical to life, suggesting other roles are in play. It is also possible that these roles for Mb are “malleable” across the animal kingdom, being more important as an O2 storage and delivery modality to long-term diving animals for instance. In addition, we have shown that oxygenated (but not deoxygenated) Mb binds fatty acids and acylcarnitines near the heme pocket, which suggests a function in sequestering lipids or preventing lipotoxicity. In this paper, we have shown lactate-Mb binding by demonstrating pH-dependency of binding of lactate to Mb, plus actions of lactate to promote offloading of O2 from the Mb molecule. Might this be yet another mechanism by which Mb’s signaling actions are modified by the in-situ muscle environment and metabolite pools, and/or a means by which Mb provides O2 under conditions in which pO2 and pH are dropping and lactate accumulation becomes most evident? Time will tell, but these findings continue to raise important questions related to Mb’s true role in metabolic regulation, and how the protein is modified by important metabolites that change with the ebb and flow of muscle and heart workload or availability of O2.

Technical Abstract: Myoglobin (Mb)-mediated oxygen (O2) delivery and dissolved O2 in the cytosol are two major sources that support oxidative phosphorylation. During intense exercise, lactate (LAC) production is elevated in skeletal muscles as a consequence of insufficient intracellular O2 supply. The latter results in diminished mitochondrial oxidative metabolism and an increased reliance on nonoxidative pathways to generate ATP. Whether or not metabolites from these pathways impact Mb-O2 associations remains to be established. In the present study, we employed isothermal titration calorimetry, O2 kinetic studies, and UV-Vis spectroscopy to evaluate the LAC affinity toward Mb (oxy- and deoxy-Mb) and the effect of LAC on O2 release from oxy-Mb in varying pH conditions (pH 6.0–7.0). Our results show that LAC avidly binds to both oxy- and deoxy-Mb (only at acidic pH for the latter). Similarly, in the presence of LAC, increased release of O2 from oxy-Mb was detected. This suggests that with LAC binding to Mb, the structural conformation of the protein (near the heme center) might be altered, which concomitantly triggers the release of O2. Taken together, these novel findings support a mechanism where LAC acts as a regulator of O2 management in Mb-rich tissues and/or influences the putative signaling roles for oxy- and deoxy-Mb, especially under conditions of LAC accumulation and lactic acidosis.