bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2024–08–25
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
  2. Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.
  1. Cell Signal. 2024 Aug 19. pii: S0898-6568(24)00321-8. [Epub ahead of print] 111353
    Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
    Yongshu Wu, Yang Yang, Xiaodong Qin, Zhixiong Zhang, Munib Ullah, Yanmin Li, Zhidong Zhang.
      The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interactions with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.
    Keywords:  Heme-regulated inhibitor; Mitochondrial proteostasis; Mitochondrial unfolded protein response; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111353
  2. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2409628121
    Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.
    Charles Bou-Nader, Swati Gaikwad, Soheila Bahmanjah, Fan Zhang, Alan G Hinnebusch, Jinwei Zhang.
      Protein kinase Gcn2 attenuates protein synthesis in response to amino acid starvation while stimulating translation of a transcriptional activator of amino acid biosynthesis. Gcn2 activation requires a domain related to histidyl-tRNA synthetase (HisRS), the enzyme that aminoacylates tRNAHis. While evidence suggests that deacylated tRNA binds the HisRS domain for kinase activation, ribosomal P-stalk proteins have been implicated as alternative activating ligands on stalled ribosomes. We report crystal structures of the HisRS domain of Chaetomium thermophilum Gcn2 that reveal structural mimicry of both catalytic (CD) and anticodon-binding (ABD) domains, which in authentic HisRS bind the acceptor stem and anticodon loop of tRNAHis. Elements for forming histidyl adenylate and aminoacylation are lacking, suggesting that Gcn2HisRS was repurposed for kinase activation, consistent with mutations in the CD that dysregulate yeast Gcn2 function. Substituting conserved ABD residues well positioned to contact the anticodon loop or that form a conserved ABD-CD interface impairs Gcn2 function in starved cells. Mimicry in Gcn2HisRS of two highly conserved structural domains for binding both ends of tRNA-each crucial for Gcn2 function-supports that deacylated tRNAs activate Gcn2 and exemplifies how a metabolic enzyme is repurposed to host new local structures and sequences that confer a novel regulatory function.
    Keywords:  GCN4 translation; Gcn2; eIF2α phosphorylation; histidyl-tRNA synthetase; yeast S. cerevisiae
    DOI:  https://doi.org/10.1073/pnas.2409628121
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