AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.

Autor: Zhai X; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Yang R; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Chu Q; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China., Guo Z; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Hou P; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Li X; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Bai C; Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China., Lu Z; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Qiao L; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Fu Y; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China., Niu J; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China., Li B; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China. bli@ccmu.edu.cn.; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. bli@ccmu.edu.cn.; Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. bli@ccmu.edu.cn.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2025 Jan 02. Date of Electronic Publication: 2025 Jan 02.
DOI: 10.1038/s41556-024-01549-x
Abstrakt: Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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