Li Xue, Luo Lin-Lin, Li Rui-Feng, Chen Chun-Lin, Sun Min, Lin Sen
Department of Ophthalmology, Daping Hospital, Army Medical Center of PLA, Army Medical University, Chongqing, China.
Department of Neurology, Xinqiao Hospital, The Second Affiliated Hospital, Army Medical University, Chongqing, China.
Aging Dis. 2023 Oct 1;14(5):1834-1852. doi: 10.14336/AD.2023.0216-1.
Lens fibrosis is one of the leading causes of cataract in the elderly population. The primary energy substrate of the lens is glucose from the aqueous humor, and the transparency of mature lens epithelial cells (LECs) is dependent on glycolysis for ATP. Therefore, the deconstruction of reprogramming of glycolytic metabolism can contribute to further understanding of LEC epithelial-mesenchymal transition (EMT). In the present study, we found a novel pantothenate kinase 4 (PANK4)-related glycolytic mechanism that regulates LEC EMT. The PANK4 level was correlated with aging in cataract patients and mice. Loss of function of PANK4 significantly contributed to alleviating LEC EMT by upregulating pyruvate kinase M2 isozyme (PKM2), which was phosphorylated at Y105, thus switching oxidative phosphorylation to glycolysis. However, PKM2 regulation did not affect PANK4, demonstrating the downstream role of PKM2. Inhibition of PKM2 in Pank4 mice caused lens fibrosis, which supports the finding that the PANK4-PKM2 axis is required for LEC EMT. Glycolytic metabolism-governed hypoxia inducible factor (HIF) signaling is involved in PANK4-PKM2-related downstream signaling. However, HIF-1α elevation was independent of PKM2 (S37) but PKM2 (Y105) when PANK4 was deleted, which demonstrated that PKM2 and HIF-1α were not involved in a classic positive feedback loop. Collectively, these results indicate a PANK4-related glycolysis switch that may contribute to HIF-1 stabilization and PKM2 phosphorylation at Y105 and inhibit LEC EMT. The mechanism elucidation in our study may also shed light on fibrosis treatments for other organs.
晶状体纤维化是老年人群白内障的主要病因之一。晶状体的主要能量底物是来自房水的葡萄糖，成熟晶状体上皮细胞（LEC）的透明度依赖糖酵解产生ATP。因此，解构糖酵解代谢重编程有助于进一步理解LEC上皮-间质转化（EMT）。在本研究中，我们发现了一种新的泛酸激酶4（PANK4）相关糖酵解机制，该机制调节LEC EMT。PANK4水平与白内障患者和小鼠的衰老相关。PANK4功能丧失通过上调在Y105位点磷酸化的丙酮酸激酶M2同工酶（PKM2）显著促进LEC EMT的缓解，从而将氧化磷酸化转换为糖酵解。然而，PKM2的调节并不影响PANK4，表明PKM2起下游作用。在Pank4基因敲除小鼠中抑制PKM2会导致晶状体纤维化，这支持了LEC EMT需要PANK4-PKM2轴这一发现。糖酵解代谢调控的缺氧诱导因子（HIF）信号通路参与PANK4-PKM2相关的下游信号传导。然而，当PANK4缺失时，HIF-1α升高独立于PKM2（S37）但依赖于PKM2（Y105），这表明PKM2和HIF-1α不参与经典的正反馈回路。总体而言，这些结果表明存在一种与PANK4相关的糖酵解开关，它可能有助于HIF-1的稳定以及PKM2在Y105位点的磷酸化，并抑制LEC EMT。我们研究中的机制阐释也可能为其他器官的纤维化治疗提供线索。
