Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells

Andrew D Beale; Edward A Hayter; Priya Crosby; Utham K Valekunja; Rachel S Edgar; Johanna E Chesham; Elizabeth S Maywood; Fatima H Labeed; Akhilesh B Reddy; Kenneth P Wright; Kathryn S Lilley; David A Bechtold; Michael H Hastings; John S O'Neill

doi:10.15252/embj.2023114164

Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells

Andrew D Beale, Edward A Hayter, Priya Crosby, Utham K Valekunja, Rachel S Edgar, Johanna E Chesham, Elizabeth S Maywood, Fatima H Labeed, Akhilesh B Reddy, Kenneth P Wright, Kathryn S Lilley, David A Bechtold, Michael H Hastings, John S O'Neill

Division of Diabetes, Endocrinology & Gastroenterology (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

Original language	English
Article number	e114164
Journal	The EMBO Journal
Volume	42
Issue number	19
Early online date	9 Aug 2023
DOIs	https://doi.org/10.15252/embj.2023114164
Publication status	Published - 4 Oct 2023

Keywords

Humans
Mice
Animals
Erythrocytes/metabolism
Hemoglobins/metabolism
Oxidation-Reduction
Heme/metabolism
Circadian Rhythm

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10.15252/embj.2023114164Licence: CC BY

Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology
Bechtold, D. (PI), Brown, T. (CoI) & Trafford, A. (CoI)
1/06/21 → 31/05/24
Project: Research

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Beale, A. D., Hayter, E. A., Crosby, P., Valekunja, U. K., Edgar, R. S., Chesham, J. E., Maywood, E. S., Labeed, F. H., Reddy, A. B., Wright, K. P., Lilley, K. S., Bechtold, D. A., Hastings, M. H., & O'Neill, J. S. (2023). Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells. The EMBO Journal, 42(19), Article e114164. https://doi.org/10.15252/embj.2023114164

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abstract = "Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.",

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AU - Beale, Andrew D

AU - Hayter, Edward A

AU - Crosby, Priya

AU - Valekunja, Utham K

AU - Edgar, Rachel S

AU - Chesham, Johanna E

AU - Maywood, Elizabeth S

AU - Labeed, Fatima H

AU - Reddy, Akhilesh B

AU - Wright, Kenneth P

AU - Lilley, Kathryn S

AU - Bechtold, David A

AU - Hastings, Michael H

AU - O'Neill, John S

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N2 - Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

AB - Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

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KW - Hemoglobins/metabolism

KW - Oxidation-Reduction

KW - Heme/metabolism

KW - Circadian Rhythm

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DO - 10.15252/embj.2023114164

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VL - 42

JO - The EMBO Journal

JF - The EMBO Journal

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M1 - e114164

ER -

Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells

Abstract

Keywords

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Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology

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