Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells

Primitive hematopoietic stem cells (pHSCs) sustain lifelong hematopoiesis through tightly regulated transitions between quiescence and activation. Circadian oscillations influence hematopoiesis; however, the mechanisms coordinating metabolic state and stem cell function daily remain incompletely defined. Here, we show that circadian cues coordinated a program of mitochondrial remodeling, metabolic reprogramming, and structural adaptation in pHSCs. At night, peak melatonin levels were associated with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and activation of DRP1 and PINK1 dependent mitophagy, resulting in enhanced long term repopulating capacity. In parallel, pHSCs exhibited increased glycolytic activity characterized by elevated glucose uptake, GLUT1 expression, AMPK phosphorylation, and HIF1α signaling. Mechanistically, mitochondrial remodeling was regulated in part by melatonin signaling, whereas glycolytic reprogramming was modulated by systemic circadian inputs, including feeding associated cues and Wnt/β-catenin signaling. FoxM1 and DRP1 contributed to mitochondrial quality control, while PGC1α dependent transcription supported compensatory mitochondrial biogenesis across the daily circadian cycle. These metabolic transitions were accompanied by dynamic changes in cell and nuclear size, linked to lamin A/C phosphorylation modulation. These coordinated processes defined a nocturnal state of enhanced stem cell fitness characterized by improved regenerative potential. Key features of glycolytic regulation were conserved in human HSCs, and in vitro melatonin treatment reduced the mitochondrial membrane potential and cell size of human pHSCs. Together, these findings establish a temporally regulated metabolic framework in which circadian cues partition mitochondrial and glycolytic programs to preserve stem cell maintenance and function, adding a new layer to pHSC metabolic physiology with clinical transplantation implications.

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Journal
Blood
Published
2026-09-21
DOI
https://doi.org/10.1182/blood.2026034660
Primary Topic
Circadian rhythm and melatonin
Type
article
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article

Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells

Amnon Buxboim, Berthold Göttgens, Arturo Simoni‐Nieves, John B. Hogenesch et al.
Blood
Circadian rhythm and melatonin
article

Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells

Amnon Buxboim, Berthold Göttgens, Arturo Simoni‐Nieves, John B. Hogenesch, Tzu-Hsuan Chang, Ping‐Chih Ho, Sarah Kinston, Regina Pekelmann Markus, Angelica Varesi, Jiffin K. Paulose, Iwo Kuciński, Priyasmita Chakrabarti, Tsvee Lapidot, Ziv Porat, You‐Yang Zhao, Stephanie Zhi-Juan Xie, Abhishek Kumar Singh, Ekaterina Petrovich‐Kopitman, José A. Cancelas, Avik Choudhuri, Órit Kollet, Leonard Ira Zon, Nicola K. Wilson, Yihao Wang, T. Yu. Smirnova, M. Haddad, John E. Dick, MS Vijayabaskar, Lizeth-Alejandra Ordonez Moreno1, Marie-Dominique Filippi
article en

Abstract

Primitive hematopoietic stem cells (pHSCs) sustain lifelong hematopoiesis through tightly regulated transitions between quiescence and activation. Circadian oscillations influence hematopoiesis; however, the mechanisms coordinating metabolic state and stem cell function daily remain incompletely defined. Here, we show that circadian cues coordinated a program of mitochondrial remodeling, metabolic reprogramming, and structural adaptation in pHSCs. At night, peak melatonin levels were associated with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and activation of DRP1 and PINK1 dependent mitophagy, resulting in enhanced long term repopulating capacity. In parallel, pHSCs exhibited increased glycolytic activity characterized by elevated glucose uptake, GLUT1 expression, AMPK phosphorylation, and HIF1α signaling. Mechanistically, mitochondrial remodeling was regulated in part by melatonin signaling, whereas glycolytic reprogramming was modulated by systemic circadian inputs, including feeding associated cues and Wnt/β-catenin signaling. FoxM1 and DRP1 contributed to mitochondrial quality control, while PGC1α dependent transcription supported compensatory mitochondrial biogenesis across the daily circadian cycle. These metabolic transitions were accompanied by dynamic changes in cell and nuclear size, linked to lamin A/C phosphorylation modulation. These coordinated processes defined a nocturnal state of enhanced stem cell fitness characterized by improved regenerative potential. Key features of glycolytic regulation were conserved in human HSCs, and in vitro melatonin treatment reduced the mitochondrial membrane potential and cell size of human pHSCs. Together, these findings establish a temporally regulated metabolic framework in which circadian cues partition mitochondrial and glycolytic programs to preserve stem cell maintenance and function, adding a new layer to pHSC metabolic physiology with clinical transplantation implications.

Blood
Northwestern University (US), University Health Network (CA), Harvard University (US), Universidade de São Paulo (BR), Hebrew University of Jerusalem (IL), Universidad Autónoma Metropolitana (MX), University of Cambridge (GB), Wellcome Sanger Institute (GB), Princess Margaret Cancer Centre (CA), Hospital Research Foundation (AU), Dana-Farber Cancer Institute (US), Ludwig Cancer Research (CH), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Weizmann Institute of Science (IL), University of Lausanne (CH)
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Circadian rhythm and melatonin
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