bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2026–02–22
three papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. De novo design of protein binders that target DELE1 to inhibit the mitochondrial stress response.
  2. The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.
  3. Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
  1. bioRxiv. 2026 Feb 12. pii: 2025.12.22.695711. [Epub ahead of print]
    De novo design of protein binders that target DELE1 to inhibit the mitochondrial stress response.
    Rui Yang, Kaiyuan Zheng, McGuire Metts, Yiluo Wang, Danyan Yin, Kevin P Li, Agnieszka A Prazmowska, David F Kashatus, Brian Kuhlman, Jie Yang.
      Mitochondrial stress activates the integrated stress response (ISR) through the mitochondrial protein DELE1, which relays stress signals to the cytosolic kinase HRI to induce ATF4. Dysregulation of DELE1-mediated signaling has been implicated in pathological conditions, yet molecular strategies to modulate DELE1 remain unavailable. Here, we report de novo designed proteins that bind DELE1, block its oligomerization, and inhibit DELE1-mediated ISR activation. Several designs form stable complexes with DELE1 and disrupt its oligomerization in vitro while preserving DELE1's ability to bind HRI. In cells, these designs suppress ATF4 induction during mitochondrial stress and impair the recovery of elongated mitochondrial morphology following transient insult. Crystal structure analysis, structural modeling, and targeted mutagenesis confirm that the designed proteins engage a critical interface required for DELE1 oligomerization. These findings establish DELE1 as a druggable target and demonstrate that de novo designed proteins offer precise tools to modulate this pathway, laying groundwork for therapeutic development.
    DOI:  https://doi.org/10.64898/2025.12.22.695711
  2. FEBS J. 2026 Feb 18.
    The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.
    Michaela Veliova, Caroline M Ferreira, Katrina P Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Anthony E Jones, Linsey Stiles, Ajit S Divakaruni, Marc Liesa, Orian S Shirihai, Marcus F Oliveira.
      Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD+ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle (GPSh), and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh, namely the oxoglutarate carrier (Ogc) and aspartate-glutamate carrier (Aralar1), had no apparent effects on respiratory rates. However, silencing either Ogc or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.
    Keywords:  energy; heat; metabolism; obesity; redox; thermogenesis
    DOI:  https://doi.org/10.1111/febs.70461
  3. Nat Metab. 2026 Feb 17.
    Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
    Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.
      Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.
    DOI:  https://doi.org/10.1038/s42255-026-01454-7
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