Non-canonical hemoglobin: An updated review on its ubiquitous expression

Hemoglobin, once thought to be exclusive to erythrocytes, has been identified to be expressed in various cell types over the past several decades. While hemoglobin's function within erythrocytes is primarily characterized as a gaseous transport molecule, its function within non-erythrocyte cells varies among different cell types, and in many cases, remains to be fully elucidated. Despite this variability, hemoglobin expression seems to broadly function as a redox modulator, whether it is involved in the hypoxic response, mitochondrial function, antioxidant balance or, like in erythrocytes, gas transport. This review provides an updated summary of the most recent discoveries of hemoglobin in non-erythrocyte cells. While discussing the function and regulation of this ubiquitous protein, we additionally compare these cell-specific details to identify commonalities throughout the diverse group of hemoglobin-expressing cells. Lastly, we discuss potential implications of non-canonical hemoglobin in various disease states such neurodegeneration, autoimmune disorders, psychological trauma, and hemoglobinopathies, while providing future directions for hemoglobin research.