bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2023–10–01
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.
  2. An amino acid mixture, enriched with Krebs cycle intermediates, enhances extracellular matrix gene expression in cultured human fibroblasts.
  1. Geroscience. 2023 Sep 25.
    Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.
    Blaise L Mariner, Antonio S Rodriguez, Olivia C Heath, Mark A McCormick.
      We have recently shown that multiple tRNA synthetase inhibitors can greatly increase lifespan in multiple models by acting through the conserved transcription factor ATF4. Here, we show that these compounds, and several others of the same class, can greatly upregulate mammalian ATF4 in cells in vitro, in a dose dependent manner. Further, RNASeq analysis of these cells pointed toward changes in protein turnover. In subsequent experiments here we show that multiple tRNA synthetase inhibitors can greatly upregulate activity of the ubiquitin proteasome system (UPS) in cells in an ATF4-dependent manner. The UPS plays an important role in the turnover of many damaged or dysfunctional proteins in an organism. Increasing UPS activity has been shown to enhance the survival of Huntington's disease cell models, but there are few known pharmacological enhancers of the UPS. Additionally, we see separate ATF4 dependent upregulation of macroautophagy upon treatment with tRNA synthetase inhibitors. Protein degradation is an essential cellular process linked to many important human diseases of aging such as Alzheimer's disease and Huntington's disease. These drugs' ability to enhance proteostasis more broadly could have wide-ranging implications in the treatment of important age-related neurodegenerative diseases.
    Keywords:  ATF-4; ATF4; Gcn4; Ubiquitin proteasome system; tRNA synthetase
    DOI:  https://doi.org/10.1007/s11357-023-00938-8
  2. Amino Acids. 2023 Sep 28.
    An amino acid mixture, enriched with Krebs cycle intermediates, enhances extracellular matrix gene expression in cultured human fibroblasts.
    Maurizio Ragni, Luca Canciani, Letizia Spataro, Chiara Ruocco, Alessandra Valerio, Enzo Nisoli.
      In the human body, the skin is one of the organs most affected by the aging process. Nutritional approaches aimed to counteract the age-induced decline of extracellular matrix (ECM) deposition could be a valuable tool to decrease the degenerative processes underlying skin aging. Here, we investigated the ability of a six-amino acid plus hyaluronic acid (6AAH) formulation enriched with tricarboxylic acid (TCA) intermediates to stimulate ECM gene expression. To this aim, human BJ fibroblasts were treated with 6AAH alone or plus succinate or malate alone or succinate plus malate (6AAHSM), and mRNA levels of several ECM markers were evaluated. 6AAHSM increased the expression of all the ECM markers significantly above 6AAH alone or plus only succinate or malate. Furthermore, in an in vitro oxidative damage model, 6AAHSM blunted the hydrogen peroxide-induced decline in ECM gene expression. Our data suggest that feeding cells with 6AAH enriched with TCAs could efficiently be employed as a non-pharmacological approach for counteracting skin aging.
    Keywords:  Aging; Amino acids; Extracellular matrix; Oxidative stress
    DOI:  https://doi.org/10.1007/s00726-023-03340-y
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