Pantothenate Kinase 4 Governs Lens Epithelial Fibrosis by Negatively Regulating Pyruvate Kinase M2-Related Glycolysis

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-1 alpha elevation was independent of PKM2 (S37) but PKM2 (Y105) when PANK4 was deleted, which demonstrated that PKM2 and HIF-1 alpha 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.

Automated summary

Lens fibrosis is a common cause of cataract in elderly individuals. This study explored the role of pantothenate kinase 4 (PANK4) and glycolytic metabolism in lens epithelial-mesenchymal transition (EMT). PANK4 levels were associated with aging and loss of function of PANK4 alleviated LEC EMT by promoting glycolysis. The PANK4-PKM2 axis was found to regulate EMT and HIF-1 stabilization, offering potential insights for fibrosis treatment in other organs.