Congratulations to Roger Shi, PhD on his publication in Free Radical Biology and Medicine!

Dr. Shi is the Joe R. and Teresa Lozano Long Distinguished Chair in Metabolic Biology and a Professor with the Department of Pharmacology and the Sam and Ann Barshop Institute for Longevity and Aging Studies.

An upstream open reading frame (5′-uORF) links oxidative stress to translational control of ALCAT1 through phosphorylation of eIF2α
Jun Zhang and Yuguang Shi
Free Radic Biol Med. 2024 Mar:214:129-136. doi: 10.1016/j.freeradbiomed.2024.02.015. Epub 2024 Feb 13.


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 ALCAT1 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 ALCAT1 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 ALCAT1 mRNAs through phosphorylation of eIF2α at Ser51.

Keywords: 5′UTR; ALCAT1; Oxidative stress; Translational control; eIF2α; uORF.

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