S-nitrosylation (SNO) of Pyruvate Kinase Isoform 2 (PKM2) at Cys49 and Cys326 is a specific hallmark of activated cardiac fibroblasts in heart failure.
SNO-PKM2 disrupts PKM2 tetramerization and reduces enzyme activity, shifting the metabolic and structural state of the cell.
Mechanistically, SNO-PKM2 promotes excessive mitochondrial fission by interfering with the actin regulatory protein gelsolin, leading to mitochondrial dysfunction and fibroblast activation.
The FDA-approved drug mitapivat and the activator TEPP-46 effectively reverse these pathways, presenting a viable therapeutic strategy for mitigating cardiac fibrosis.
Background
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