Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.
Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.
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DOI：
10.1016/j.jacbts.2023.03.014
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发表时间：
2023-09
影响因子：
9.7
通讯作者：
Santulli, Gaetano
中科院分区：
文献类型：
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作者：
Gambardella, Jessica;Jankauskas, Stanislovas S.;Kansakar, Urna;Varzideh, Fahimeh;Avvisato, Roberta;Prevete, Nella;Sidoli, Simone;Mone, Pasquale;Wang, Xujun;Lombardi, Angela;Santulli, Gaetano
关键词：
我们提供了一套全面的检测方法，使用来自缺血后HF患者和健康对照受试者的人类心脏标本、HF小鼠模型以及离体和体外机制研究。我们在组蛋白3的水平上鉴定了染色质的特定表观遗传修饰，即赖氨酸27的双甲基化和赖氨酸36的单甲基化（H3_K27me2K36me1），其在所有上述设置中一致地由缺血性损伤诱导。H3_K27me2K36me1介导缺血诱导的PGC 1 α转录抑制，PGC 1 α是线粒体功能和生物发生的主要调节因子。通过用酮体BHB处理，增强的H3_K27me2K36me1和由PGC 1 α下调引起的线粒体功能障碍均显著减弱。缺血性心脏病是世界范围内死亡的主要原因。然而，这种疾病背后的确切分子过程尚不完全清楚。本研究包括一组全面协调的体内和体外实验，使用来自缺血后心力衰竭（HF）患者和健康对照受试者的人心脏标本、HF小鼠模型和细胞系统。这些方法首次确定了一种适应不良的染色质重塑的特定模式，即组蛋白3在赖氨酸27处的双重甲基化和赖氨酸36处的单一甲基化（H3_K27me2K36me1）在所有这些环境中一致地由缺血性损伤诱导：人HF;鼠HF;和体外模型。从机制上讲，这项工作表明，这种组蛋白修饰介导了缺血诱导的PPARG辅激活因子1α（PGC 1 α）的转录抑制，这是线粒体功能和生物发生的主要调节因子。有趣的是，通过β-羟基丁酸酯（人体中最丰富的酮体）处理，增强的H3_K27me2K36me1和随后由PGC 1 α下调引起的线粒体功能障碍均显著减弱，揭示了一种将代谢与基因表达偶联的新途径。总之，这些发现确立了适应不良的染色质重塑是缺血后心脏损伤的关键机制，在功能上受酮体调节。
We provide a comprehensive set of assays using human cardiac specimens from patients with postischemic HF and healthy control subjects, a murine model of HF, and mechanistic studies ex vivo and in vitro. We identified a specific epigenetic modification of the chromatine, at the level of histone 3, namely a double methylation of lysine 27 and a single methylation of lysine 36 (H3_K27me2K36me1), which is consistently induced by ischemic injury in all the above-mentioned settings. H3_K27me2K36me1 mediates the ischemia-induced transcriptional repression of PGC1α, master regulator of mitochondrial function and biogenesis. Both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction caused by the down-regulation of PGC1α are significantly attenuated by the treatment with the ketone body BHB. Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.
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DOI：
10.1073/pnas.96.14.8144
发表时间：
1999-07-06
影响因子：
11.1
作者：
Narula, J;Pandey, P;Kharbanda, S
通讯作者：
Kharbanda, S
影响因子：
5
作者：
Yu, Yongsheng;Yu, Yunhua;Zhao, Xianxian
通讯作者：
Zhao, Xianxian
影响因子：
37.8
作者：
Nielsen, Roni;Moller, Niels;Wiggers, Henrik
通讯作者：
Wiggers, Henrik
肿瘤代谢，生酮饮食和β-羟基丁酸：辅助脑肿瘤疗法的新方法。
影响因子：
4.8
作者：
Woolf EC;Syed N;Scheck AC
通讯作者：
Scheck AC
影响因子：
64.8
作者：
通讯作者：
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