bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–07–13
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
  2. MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
  1. Sci Adv. 2025 Jul 11. 11(28): eadw1883
    Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
    Shruthi Krishnan, Ana Lima, Sizhe Tan, Ying Thong Low, Salvador Perez Montero, Aida Di Gregorio, Adrian Perez Barreto, Sarah Bowling, Karen Vousden, Tristan A Rodriguez.
      Cell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that l-proline is a key amino acid sensed by the ISR and that proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified tissue-sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.
    DOI:  https://doi.org/10.1126/sciadv.adw1883
  2. J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):
    MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
    Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.
      Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.
    Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH
    DOI:  https://doi.org/10.1242/jcs.263701
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