Acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) is an enzyme that promotes mitochondrial dysfunction by catalyzing pathological remodeling of cardiolipin. Upregulation of ALCAT1 protein expression by oxidative stress is implicated in the pathogenesis of age-related metabolic diseases, but the underlying molecular mechanisms remain elusive. In this study, we identified a highly conserved upstream open reading frame (uORF) at the 5′-untranslated region (5′-UTR) of mRNA as a key regulator of ALCAT1 expression in response to oxidative stress. We show that the uORF serves as a decoy that prevents translation initiation of ALCAT1 under homeostatic condition. The inhibitory activity of the uORF on mRNA translation is mitigated by oxidative stress but not ER stress, which requires the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Consequently, ablation of uORF or eIF2α phosphorylation at Ser51 renders ALCAT1 protein expression unresponsive to induction by oxidative stress. Taken together, our data show that the uORF links oxidative stress to translation control of mRNAs through phosphorylation of eIF2α at Ser51.

中文翻译：

---

上游开放阅读框 (5′-uORF) 通过 eIF2α 磷酸化将氧化应激与 ALCAT1 的翻译控制联系起来

酰基辅酶A：溶心磷脂酰基转移酶 1 (ALCAT1) 是一种通过催化心磷脂病理性重塑而促进线粒体功能障碍的酶。氧化应激导致的 ALCAT1 蛋白表达上调与年龄相关代谢疾病的发病机制有关，但潜在的分子机制仍然难以捉摸。在这项研究中，我们在 mRNA 5′非翻译区 (5′-UTR) 上发现了一个高度保守的上游开放阅读框 (uORF)，它是 ALCAT1 表达响应氧化应激的关键调节因子。我们发现 uORF 作为诱饵，在稳态条件下阻止 ALCAT1 的翻译起始。uORF 对 mRNA 翻译的抑制活性会因氧化应激而减弱，但不会因内质网应激而减弱，内质网应激需要真核翻译起始因子 2α (eIF2α) 的磷酸化。因此，uORF 或 eIF2α Ser51 磷酸化的消除使 ALCAT1 蛋白表达对氧化应激的诱导无反应。综上所述，我们的数据表明 uORF 通过 eIF2α Ser51 的磷酸化将氧化应激与 mRNA 的翻译控制联系起来。