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bioRxiv · 10.1101/2022.08.02.502446

Pantothenate Kinase 4 Governs Lens Epithelial Fibrosis by Negatively Regulating PKM2 Related Glycolysis

Li, X.·Luo, L.-L.·Hu, Q.-M.·Chen, X.·Li, R.-F.·Chen, C.-L.·Sun, M.·Lin, S.
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Abstract

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

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Li, X., Luo, L.-L., Hu, Q.-M., Chen, X., Li, R.-F., Chen, C.-L., Sun, M., Lin, S.. 2022-08-03. Pantothenate Kinase 4 Governs Lens Epithelial Fibrosis by Negatively Regulating PKM2 Related Glycolysis. https://doi.org/10.1101/2022.08.02.502446

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