Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage

Abstract

Objective Ionizing radiation (IR) causes cardiac senescence, which eventually manifests as radiation-induced heart damage (RIHD). This study is aimed at exploring the mechanisms underlying IR-induced senescence using acetylation proteomics. Methods Irradiated mouse hearts and H9C2 cells were harvested for senescence detection. Acetylation proteomics was used to investigate alterations in lysine acetylation. Atp5f1c acetylation after IR was verified using coimmunoprecipitation (Co-IP). Atp5f1c lysine 55 site acetylation (Atp5f1c K55-Ac) point mutation plasmids were used to evaluate the influence of Atp5f1c K55-Ac on energy metabolism and cellular senescence. Deacetylation inhibitors, plasmids, and siRNA transfection were used to determine the mechanism of Atp5f1c K55-Ac regulation. Results The mice showed cardiomyocyte and cardiac aging phenotypes after IR. We identified 90 lysine acetylation sites from 70 protein alterations in the heart in response to IR. Hyperacetylated proteins are primarily involved in energy metabolism. Among them, Atp5f1c was hyperacetylated, as confirmed by Co-IP. Atp5f1c K55-Ac decreased ATP enzyme activity and synthesis. Atp5f1c K55 acetylation induced cardiomyocyte senescence, and Sirt4 and Sirt5 regulated Atp5f1c K55 deacetylation. Conclusion Our findings reveal a mechanism of RIHD through which Atp5f1c K55-Ac leads to cardiac aging and Sirt4 or Sirt5 modulates Atp5f1c acetylation. Therefore, the regulation of Atp5f1c K55-Ac might be a potential target for the treatment of RIHD.

Spatially resolved transcriptomic profiling of placental development in dairy cow

“…PRP4 showed high expression in UNCs_7, while CYP19A1 and ATP5F1C were highly expressed in UNCs_1. The CYP19A1 gene, which encodes aromatase, is involved in the biosynthesis of estrogens, required for successful establishment and maintenance of pregnancy and proper fetal development ( Chatuphonprasert et al, 2018 ), whereas the ATP5F1C gene is involved in the assembly and function of adenosine triphosphate (ATP) synthase, playing a crucial role in cellular energy metabolism ( Zeng et al, 2022 ). The UNCs_2 subpopulation, in addition to expressing typical trophoblast cell markers, also expressed transcription factors ( CITED1 , CDX2 , GATA3 , TCF7L2 ), proliferation markers ( MKI67 , MCM2 ), and cell cycle markers ( CCNA1 , CCNA2 , CCNB1 , CCNB2 , CCNE2 , CCNF , CCNG1 , CCNG2 , CDKN1B , CDKN1C ), and was thus defined as proliferative UNCs.…”

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology

“…These included an elevated expression of senescence-associated β-galactosidase (SA-β-Gal), upregulated levels of cell cycle inhibitory proteins p16 and p21, and increased expression of transcripts coding for some SASP factors, like IL-6, CCL-2, MMP-2, Col3a1, and CTGF in the irradiated H9C2 cells. Significantly, these cellular changes corresponded to the formation of senescence phenotype in the heart tissue in vivo, in which IR treatment resulted in the telomere shortening and even more excessive SASP formation [ 60 ].…”

“…One of the hyperacetylated targets, Atp5f1c (the lysine 55 site), which is closely related to cell energetics as an element of an ATP synthase complex [ 63 ], appeared to be causatively connected with the development of IR-driven senescence phenotype in H9C2 cells. Hypothetically, it could also contribute to fibrotic changes in the heart muscle in vivo [ 60 ].…”