Zhang Zhi-Ling, Ren Shu-Ting, Yang Wan-Jie, Xu Xiao-Wen, Zhao Shi-Min, Fang Ke-Fei, Lin Yan, Yuan Yi-Yuan, Zhang Xiao-Jin, Chen Yun-Qin, Xu Wei
Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China.
Cell Death Discov. 2025 Apr 29;11(1):209. doi: 10.1038/s41420-025-02501-0.
Lactate, a metabolite which is elevated in various developmental and pathological processes, exerts its signal through alanyl tRNA synthetases (AARS)-catalyzed protein lactylation. Herein, we report that elevated lactate and gain-of-function mitochondrial AARS (AARS2) mutations-induced hyper-lactylation promotes premature ovarian insufficiency (POI). Serum lactate is elevated in POI patients. POI-driving AARS2 mutations gain lactyltransferase activity. AARS2 lactylates and inactivates carnitine palmitoyl transferase 2 (CPT2), resulting in FFA accumulation that activates peroxisome proliferator-activated receptor γ (PPARγ), and potentiates follicle-stimulating hormone (FSH) to initiate follicle development. These, in synergy with the anabolites accumulation effects of AARS2, promoted lactylation-induced PDHA1 inactivation promote granular cell (GC) proliferation and primordial follicle development. GC-specific AARS2 overexpression does not affect primordial follicle number but speed up follicle depletion. AARS2 ablation or lactylation-inhibiting β-alanine treatments can prevent folliculogenesis and POI traits in mouse. These findings reveal that lactate signal drives follicle development, and inhibiting lactate signal could treat/prevent POI.
乳酸是一种在各种发育和病理过程中水平升高的代谢产物，它通过丙氨酰-tRNA合成酶（AARS）催化的蛋白质乳酰化作用来传递信号。在此，我们报告，乳酸水平升高和功能获得性线粒体AARS（AARS2）突变诱导的过度乳酰化会促进早发性卵巢功能不全（POI）。POI患者的血清乳酸水平升高。驱动POI的AARS2突变获得了乳酰转移酶活性。AARS2使肉碱棕榈酰转移酶2（CPT2）发生乳酰化并使其失活，导致游离脂肪酸（FFA）积累，从而激活过氧化物酶体增殖物激活受体γ（PPARγ），并增强促卵泡激素（FSH）以启动卵泡发育。这些与AARS2的合成代谢产物积累效应协同作用，促进乳酰化诱导的丙酮酸脱氢酶E1α亚基（PDHA1）失活，进而促进颗粒细胞（GC）增殖和原始卵泡发育。GC特异性AARS2过表达不影响原始卵泡数量，但会加速卵泡耗竭。AARS2基因敲除或抑制乳酰化的β-丙氨酸处理可预防小鼠的卵泡发生和POI特征。这些发现揭示了乳酸信号驱动卵泡发育，抑制乳酸信号可以治疗/预防POI。
