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c-Abl tyrosine kinase inhibition attenuate oxidative stress-induced pancreatic β-Cell dysfunction via glutathione antioxidant system

  • Udayakumar Karunakaran
    Correspondence
    Reprint requests: Udayakumar Karunakaran, Innovative Center for Aging Research, Yeungnam University Medical Center, 170 Hyeonchung-ro, Daegu 42415, Republic of Korea.
    Affiliations
    Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea
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  • Suma Elumalai
    Affiliations
    Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea
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  • Jun Sung Moon
    Correspondence
    Reprint requests: Kyu Chang Won, Jun Sung Moon, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Daegu 42415, Republic of Korea.
    Affiliations
    Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea

    Yeungnam University College of Medicine, Daegu, Republic of Korea
    Search for articles by this author
  • Kyu Chang Won
    Correspondence
    Reprint requests: Kyu Chang Won, Jun Sung Moon, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Daegu 42415, Republic of Korea.
    Affiliations
    Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea

    Yeungnam University College of Medicine, Daegu, Republic of Korea
    Search for articles by this author
      Chronic oxidative stress, which is caused by aberrant non-receptor tyrosine kinase (c-Abl) signaling, plays a key role in the progression of β-cell loss in diabetes mellitus. Recent studies, however, have linked ferroptotic-like death to the β-cell loss in diabetes mellitus. Here, we report that oxidative stress-driven reduced/oxidized glutathione (GSH/GSSG) loss and proteasomal degradation of glutathione peroxidase 4 (GPX4) promote ferroptotic-like cell damage through increased lipid peroxidation. Mechanistically, treatment with GNF2, a non-ATP competitive c-Abl kinase inhibitor, selectively preserves β-cell function by inducing the orphan nuclear receptor estrogen-related receptor gamma (ERRγ). ERRγ-driven glutaminase 1 (GLS1) expression promotes the elevation of the GSH/GSSG ratio, and this increase leads to the inhibition of lipid peroxidation by GPX4. Strikingly, pharmacological inhibition of ERRγ represses the expression of GLS1 and reverses the GSH/GSSG ratio linked to mitochondrial dysfunction and increased lipid peroxidation mediated by GPX4 degradation. Inhibition of GLS1 suppresses the ERRγ agonist DY131-induced GSH/GSSG ratio linked to ferroptotic-like death owing to the loss of GPX4. Furthermore, immunohistochemical analysis showed enhanced ERRγ and GPX4 expression in the pancreatic islets of GNF2-treated mice compared to that in streptozotocin-treated mice. Altogether, our results provide the first evidence that the orphan nuclear receptor ERRγ-induced GLS1 expression augments the glutathione antioxidant system, and its downstream signaling leads to improved β-cell function and survival under oxidative stress conditions.

      Abbreviations:

      ERRγ (Estrogen-related receptor gamma), GLS1 (Glutaminase 1), GSH (Glutathione)
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