Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, Jiangxi Province, China.
Oxid Med Cell Longev. 2022 Sep 15;2022:4155565. doi: 10.1155/2022/4155565. eCollection 2022.
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.
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.
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.
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.
电离辐射（IR）会引起心脏衰老，最终表现为放射性心脏损伤（RIHD）。本研究旨在通过乙酰化蛋白质组学探讨 IR 诱导衰老的机制。
采集辐照小鼠心脏和 H9C2 细胞进行衰老检测。使用乙酰化蛋白质组学研究赖氨酸乙酰化的变化。使用免疫共沉淀（Co-IP）验证 IR 后 Atp5f1c 的乙酰化。使用 Atp5f1c 赖氨酸 55 位乙酰化（Atp5f1c K55-Ac）点突变质粒评估 Atp5f1c K55-Ac 对能量代谢和细胞衰老的影响。使用去乙酰化抑制剂、质粒和 siRNA 转染确定 Atp5f1c K55-Ac 调节的机制。
IR 后小鼠表现出心肌细胞和心脏衰老表型。我们从 IR 后心脏中 70 种蛋白质变化中鉴定出 90 个赖氨酸乙酰化位点。高乙酰化蛋白主要参与能量代谢。其中，Atp5f1c 被 Co-IP 证实为高乙酰化。Atp5f1c K55-Ac 降低 ATP 酶活性和合成。Atp5f1c K55 乙酰化诱导心肌细胞衰老，Sirt4 和 Sirt5 调节 Atp5f1c K55 去乙酰化。
我们的研究结果揭示了 RIHD 的一种机制，即 Atp5f1c K55-Ac 导致心脏衰老，Sirt4 或 Sirt5 调节 Atp5f1c 乙酰化。因此，调节 Atp5f1c K55-Ac 可能是治疗 RIHD 的潜在靶点。
