bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2026–01–18
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Coenzyme A mitigates cystine-deprivation-induced ferroptosis by suppressing the iron-starvation response.
  2. Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
  1. FEBS J. 2026 Jan 16.
    Coenzyme A mitigates cystine-deprivation-induced ferroptosis by suppressing the iron-starvation response.
    Mingjun Tan, Yunzhan Li, Lei Sang, Min Wang, Qin Li, Zekun Li, Dongxiao Sun, Xiuchao Wang, Shengyu Yang.
      The labile iron pool in the cell is required for ferroptosis, a form of regulated cell death resulting from excessive lipid peroxidation and membrane damage. Glutathione (GSH) is critical for lipid-peroxide scavenging, and cysteine is the rate-limiting amino acid in GSH synthesis. Cysteine metabolism intricately intertwines with iron metabolism, either directly by participating in assembly of the iron-sulfur cluster or indirectly through the pantothenate pathway and coenzyme A (CoA) synthesis. However, the regulation of iron homeostasis in cystine (Cys2)-deprivation-induced ferroptosis is poorly understood. Here, we show that Cys2 deprivation promotes ferroptosis, at least in part, by activating the iron-starvation response (ISR), and CoA can mitigate ferroptosis by suppressing the ISR. Mechanistically, Cys2 deprivation promotes the oxidation of cytosolic iron-sulfur clusters to activate the ISR; CoA and related small-molecule thiols in the pantothenate pathway suppress the ISR and ferroptosis by preventing the oxidation of iron-sulfur clusters in Cys2-deprived cells. Our findings provide important insight into the regulation of the ISR in Cys2-deprivation-induced ferroptosis, and show that CoA can protect cells from Cys2-deprivation-induced ferroptosis by suppressing the ISR.
    Keywords:  Coenzyme A; cysteine; cystine‐deprivation; ferroptosis; iron‐starvation response; iron–sulfur cluster; pantothenate pathway
    DOI:  https://doi.org/10.1111/febs.70411
  2. Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00501-4. [Epub ahead of print]90 103988
    Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
    Viktor Antonsson Garellick, Nadia Gul, Parvin Horrieh, Dyar Mustafa, Angana A H Patel, Martin Dankis, Samantha W Alvarez, Johanna Berndtson, Saeed Mahdavi, Maria Schwarz, Andreas Persson, Fikret Zahirovic, Clotilde Wiel, Volkan I Sayin, Per Lindahl.
      Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.
    Keywords:  Amino acids; Ferroptosis; Glutathione; Integrated stress response; Lung cancer; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.redox.2025.103988
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