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

Lens fibrosis is one of the leading causes of cataract. Though the epithelial-mesenchymal transition (EMT) causes anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO) which could be eliminated by surgery, yet lacks effective drug, and the mechanism elucidation which may shed on light on other organ fibrosis treatment. In current study, we discovered a novel mechanism that regulate lens epithelial cell (LEC) EMT. Firstly, pantothenate kinase 4 (PANK4) level is corelated with aging in cataract patients and mice. Loss of function of PANK4 significantly contribute to alleviate the EMT of LECs by upregulating PKM2 which was phosphorylated at Y105 residue thus switching oxidative phosphorylation to glycolysis. However, PKM2 regulation did not affect PANK4 which demonstrate the downstream role of PKM2. Inhibition of PKM2 in Pank4−/− mice cause lens fibrosis, which strengthen the results that PANK4-PKM2 axis is required for LEC EMT. It was also found glycolytic governed HIF signaling involves in the PANK4-PKM2 related downstream signaling. However, HIF-1 elevation is independent of PKM2(S37) but Y105 residue when PANK4 deleted, which demonstrated PKM2 and HIF-1 not involve in a classic positive feedback loop. Collectively, these results indicated a novel PANK4 related glycolysis switch which may contribute to HIF-1 stabilization and PKM2 phosphorylation at Y105, and inhibit the LEC EMT process.