Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Biochim Biophys Acta Mol Cell Res. 2024 Dec;1871(8):119825. doi: 10.1016/j.bbamcr.2024.119825. Epub 2024 Aug 19.
Metabolic responses to cellular stress are pivotal in cell ferroptosis, with mitophagy serving as a crucial mechanism in both metabolic processes and ferroptosis. This study aims to elucidate the effects of high glucose on cardiomyocytes (CMs) and cardiac fibroblasts (CFs) regarding ferroptosis and to uncover the underlying mechanisms involved. We examined alterations in glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and mitophagy, which are essential for metabolic adaptations and ferroptosis. High glucose exposure induced ferroptosis specifically in CMs, while CFs exhibited resistance to ferroptosis, increased glycolytic activity, and no change in OXPHOS. Moreover, high glucose treatment enhanced mitophagy and upregulated mitochondrial ferritin (FTMT). Notably, the combination of FTMT and the autophagy-related protein nuclear receptor coactivator 4 (NCOA4) increased under high glucose conditions. Silencing FTMT significantly impeded mitophagy and eliminated ferroptosis resistance in CFs cultured under high glucose conditions. The transcription factor forkhead box A1 (FOXA1) was upregulated in CFs upon high glucose exposure, playing a crucial role in the increased expression of FTMT. Within the 5'-flanking sequence of the FTMT mRNA, approximately -500 nt from the transcription initiation site, three putative FOXA1 binding sites were identified. High glucose augmented the binding affinity between FOXA1 and these sequences, thereby promoting FTMT transcription. In summary, high glucose upregulated FOXA1 expression and stimulated FTMT promoter activity in CFs, thereby promoting FTMT-dependent mitophagy and conferring ferroptosis resistance in CFs.
细胞应激的代谢反应在细胞铁死亡中起着关键作用，其中线粒体自噬既是代谢过程又是铁死亡的重要机制。本研究旨在阐明高糖对心肌细胞（CMs）和心脏成纤维细胞（CFs）铁死亡的影响，并揭示其潜在机制。我们研究了糖酵解、线粒体氧化磷酸化（OXPHOS）和线粒体自噬的变化，这些变化对于代谢适应和铁死亡至关重要。高糖暴露特异性诱导 CMs 发生铁死亡，而 CFs 则表现出对铁死亡的抗性、增加的糖酵解活性和 OXPHOS 无变化。此外，高糖处理增强了线粒体自噬并上调了线粒体铁蛋白（FTMT）。值得注意的是，FTMT 和自噬相关蛋白核受体共激活因子 4（NCOA4）的组合在高糖条件下增加。沉默 FTMT 显著抑制了高糖培养的 CFs 中的线粒体自噬并消除了铁死亡抗性。高糖暴露后 CFs 中的叉头框 A1（FOXA1）转录因子上调，在 FTMT 的表达增加中起关键作用。在 FTMT mRNA 的 5'-侧翼序列中，从转录起始位点约-500nt 处，鉴定出三个潜在的 FOXA1 结合位点。高糖增强了 FOXA1 与这些序列的结合亲和力，从而促进了 FTMT 的转录。总之，高糖上调了 CFs 中的 FOXA1 表达并刺激了 FTMT 启动子活性，从而促进了 CFs 中依赖 FTMT 的线粒体自噬并赋予了铁死亡抗性。
