Zhai Xuewei, Yang Ronghui, Chu Qiaoyun, Guo Zihao, Hou Pengjiao, Li Xuexue, Bai Changsen, Lu Ziwen, Qiao Luxin, Fu Yanxia, Niu Jing, Li Binghui
Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Nat Cell Biol. 2025 Jan;27(1):141-153. doi: 10.1038/s41556-024-01549-x. Epub 2025 Jan 2.
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.
葡萄糖代谢已得到广泛研究，但葡萄糖衍生的排泄性甘油的作用仍不清楚。在这里，我们表明缺氧会诱导NADH积累以促进甘油排泄，并且该途径持续消耗NADH，从而减弱其积累和还原应激。醛缩酶B通过与3-磷酸甘油脱氢酶GPD1和GPD1L形成复合物来参与甘油生物合成。在缺氧条件下，阻断GPD1、GPD1L或3-磷酸甘油磷酸酶会加剧还原应激并抑制细胞增殖以及体内肿瘤生长。这些酶的过表达会增加甘油排泄，但由于能量应激，在缺氧条件下仍会降低细胞活力和肿瘤增殖。AMPK使醛缩酶B失活，以减轻消耗ATP的甘油合成，缓解NADH积累引起的能量危机。因此，甘油生物合成/排泄调节还原应激和能量应激之间的平衡。此外，这种调节模式似乎在还原应激驱动的转变中普遍存在，增强了我们对代谢复杂性的理解并指导肿瘤治疗。
