SF3A2 deacetylation at lysin 10 mitigates myocardial pathological remodeling by reprogramming cardiomyocyte metabolism
Guo, R.; Zhang, Z.; Zhang, H.; Yang, Y.; Qiao, M.; Zhang, J.; Wang, Y.; Chen, J.; Li, J.; Wu, M.; Yang, K.; Qing, Y.; Dong, H.; Li, X.; Zhao, D.; Huang, Q.
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BackgroundDysregulation of splicing factor-mediated pre-mRNA alternative splicing (AS) underlies the progression of complex diseases, but the specific involvement of AS in myocardial pathological remodeling remains unclear. This study aimed to elucidate the role of splicing factor 3A, subunit 2 (SF3A2) in the development of myocardial pathological remodeling by regulating AS and its effect on metabolic reprogramming. MethodsWe evaluated the function and mechanism of SF3A2 in myocardial pathological remodeling using murine models induced by myocardial infarction (MI) and isoproterenol. The gain- and loss-of-function models (AAV9-cTNT delivery-mediated knock-in and lentivirus-mediated knockdown) combined with acetylomics, metabolomics, lipidomics, 13C-glucose tracing and immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (IP-MS) analyses were used to demonstrate the mechanism of SIRT7-mediated SF3A2 deacetylation at lysin 10 (K10). Unbiased RNA sequencing and AS analysis were conducted to identify the downstream effector of SF3A2. ResultsSF3A2 acetylation at lysine 10 was upregulated in cardiomyocytes in response to myocardial pathological remodeling. Functionally, the knock-in of a deacetylation-mimetic SF3A2 (K10R) mutant attenuated myocardial hypertrophy, fibrosis, and improved heart function. These phenotypes were accompanied by a redirection of glucose flux from anaerobic glycolysis to the TCA cycle, along with a promotion of fatty acid {beta}-oxidation by inhibiting CD36 translocation and decreasing ACLY activity. Mechanistically, SF3A2 mitigated metabolic reprogramming and mitochondrial dysfunction by regulating Nnt AS, a process involving the SF3A2-interacting protein Ddx1. IP-MS further identified SIRT7 as the deacetylase for SF3A2, which was found to be activated by ginsenoside Rg1 in a high-throughput screen, leading to improved heart function. ConclusionsOverall, our findings establish the SIRT7-SF3A2-Nnt axis as a critical regulator in metabolic reprogramming to delay pathological myocardial remodeling. Promoting SF3A2 deacetylation, mediated by AAV9 delivery or pharmacological activation of SIRT7, improved heart function, suggesting its potential as a therapeutic target for pathological myocardial remodeling.
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