A versatile delivery vehicle for cellular oxygen and fuels, or metabolic sensor? – A review and perspective on the functions of myoglobin

Authors: ADEPU, KIRAN - Arkansas Children'S Nutrition Research Center (ACNC); ANISHKIN, ANDRIY - University Of Maryland; ADAMS, SEAN - University Of California, Davis; CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Physiological Reviews
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/1/2024
Publication Date: 5/2/2024
Citation: Adepu, K.K., Anishkin, A., Adams, S.H., Chintapalli, S.V. 2024. A versatile delivery vehicle for cellular oxygen and fuels, or metabolic sensor? – A review and perspective on the functions of myoglobin. Physiological Reviews. https://doi.org/10.1152/physrev.00031.2023.
DOI: https://doi.org/10.1152/physrev.00031.2023

Interpretive Summary: Myoglobin, an age old heme containing cytoplasmic protein, functionally well known as a transient oxygen-storage and transporter protein, primarily expressed in heart and skeletal muscles, is capable of rapid release of O2 during the periods of hypoxia or anoxia. It is one of foremost structurally discovered globin family protein. For the past 50 years, many investigators are constantly exploring wide-range of physiological functions and metabolic regulation activities of myoglobin. Use of advanced genetic engineering tools and molecular techniques revealed important new insights and provided additional functions of myoglobin, such as a nitric oxide and reactive O2 species scavenger. Intriguingly, several researchers are taking advantage of the emerging state-of-the art technologies to further unravel key metabolic functions of this ever fascinating metalloprotein; that might play a key role in addressing necessary solutions to several metabolic disorders, coupled with other tissue globins and cellular metabolites. This article reviews a different perspective of this vastly studied hemoprotein readdressing its old functions, and addressing new ones, particularly in transporting fatty acids, biochemical pathway metabolites for key functioning of cellular metabolism. Finally, the recent experimental evidences to redefine our understanding on the physiological role of Mb function will be emphasized and opens a new window of research that warrants future investigation.

Technical Abstract: The canonical view of the primary physiological function of myoglobin (Mb) is that it is a tissue oxygen (O2) transporter supporting mitochondrial oxidative phosphorylation, offloading O2 as the tissue O2 partial pressure (pO2) drops. However, accumulating evidence suggests that this paradigm is too narrow, especially in the light of recent findings supporting plausible functions for Mb in lipid trafficking and sequestration, and binding of small molecules such as lactate, pyruvate, glucose, polyamines and glutathione. Data from Mb knockout mice and biochemical models suggests additional metabolic roles for Mb beyond supply of O2 for oxidative phosphorylation, including regulation of nitric oxide (NO) pools, thermogenic brown adipose tissue (BAT) function, and serving as an O2-sensor that modulates intracellular O2- and NO-responsive molecular signaling pathways. These paradigm shifts reflect a fundamental change in how oxidative metabolism and regulation are viewed in skeletal muscle, heart, and BAT. Herein, we review established and emerging roles for Mb in physiology, and present working models illustrating the possible importance of interactions between Mb and small molecule metabolites.