bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2024–01–07
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
  2. Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells.
  1. EMBO J. 2024 Jan 02.
    Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
    Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.
      Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.
    Keywords:  Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase
    DOI:  https://doi.org/10.1038/s44318-023-00001-4
  2. Cell Rep. 2023 Dec 28. pii: S2211-1247(23)01627-3. [Epub ahead of print]43(1): 113615
    Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells.
    Mehdi Amiri, Stephen J Kiniry, Anthony P Possemato, Niaz Mahmood, Tayebeh Basiri, Catherine R Dufour, Negar Tabatabaei, Qiyun Deng, Michael A Bellucci, Keerthana Harwalkar, Matthew P Stokes, Vincent Giguère, Randal J Kaufman, Yojiro Yamanaka, Pavel V Baranov, Soroush Tahmasebi, Nahum Sonenberg.
      The integrated stress response (ISR) is critical for cell survival under stress. In response to diverse environmental cues, eIF2α becomes phosphorylated, engendering a dramatic change in mRNA translation. The activation of ISR plays a pivotal role in the early embryogenesis, but the eIF2-dependent translational landscape in pluripotent embryonic stem cells (ESCs) is largely unexplored. We employ a multi-omics approach consisting of ribosome profiling, proteomics, and metabolomics in wild-type (eIF2α+/+) and phosphorylation-deficient mutant eIF2α (eIF2αA/A) mouse ESCs (mESCs) to investigate phosphorylated (p)-eIF2α-dependent translational control of naive pluripotency. We show a transient increase in p-eIF2α in the naive epiblast layer of E4.5 embryos. Absence of eIF2α phosphorylation engenders an exit from naive pluripotency following 2i (two chemical inhibitors of MEK1/2 and GSK3α/β) withdrawal. p-eIF2α controls translation of mRNAs encoding proteins that govern pluripotency, chromatin organization, and glutathione synthesis. Thus, p-eIF2α acts as a key regulator of the naive pluripotency gene regulatory network.
    Keywords:  Stem cell research; embryonic stem cells; p-eIF2α; pluripotency; ribosome profiling; translational control
    DOI:  https://doi.org/10.1016/j.celrep.2023.113615
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