bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2024–01–14
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
  2. Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners.
  1. Front Aging Neurosci. 2023 ;15 1326127
    O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
    Ibtihal M Alghusen, Marisa S Carman, Heather Wilkins, Sophiya John Ephrame, Amy Qiang, Wagner B Dias, Halyna Fedosyuk, Aspin R Denson, Russell H Swerdlow, Chad Slawson.
       Background: Accumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer's disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.
    Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.
    Results: We show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer's Disease mice model. The same results are seen in a human in vitro model of AD.
    Conclusion: Together, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt.
    Keywords:  Alzheimer’s disease; O-GlcNAc; activating transcription factor 4 (ATF4); integrated stress response; mitochondrial stress
    DOI:  https://doi.org/10.3389/fnagi.2023.1326127
  2. Nat Commun. 2024 Jan 11. 15(1): 473
    Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners.
    Pankaj Sharma, Elena Maklashina, Markus Voehler, Sona Balintova, Sarka Dvorakova, Michal Kraus, Katerina Hadrava Vanova, Zuzana Nahacka, Renata Zobalova, Stepana Boukalova, Kristyna Cunatova, Tomas Mracek, Hans K Ghayee, Karel Pacak, Jakub Rohlena, Jiri Neuzil, Gary Cecchini, T M Iverson.
      Complex II (CII) activity controls phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, cancer metabolism, immune activation, and ischemia-reperfusion injury. CII activity can be regulated at the level of assembly, a process that leverages metastable assembly intermediates. The nature of these intermediates and how CII subunits transfer between metastable complexes remains unclear. In this work, we identify metastable species containing the SDHA subunit and its assembly factors, and we assign a preferred temporal sequence of appearance of these species during CII assembly. Structures of two species show that the assembly factors undergo disordered-to-ordered transitions without the appearance of significant secondary structure. The findings identify that intrinsically disordered regions are critical in regulating CII assembly, an observation that has implications for the control of assembly in other biomolecular complexes.
    DOI:  https://doi.org/10.1038/s41467-023-44563-7
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