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<p>Diabetic retinopathy (DR) is the leading cause of blindness in diabetic patients, in which high glucose (HG)-induced Müller cell activation constitutes a central pathological event. This study aimed to untangle the critical role and mechanism of mitochondrial fission in this process. We found that under HG conditions, the level of p-Drp1 was significantly elevated (<i>P</i> &lt; 0.05), driving excessive mitochondrial fission. Functional experiments confirmed that artificially enhancing mitochondrial fission directly inhibited the Hippo signaling pathway (levels of core proteins p-MST1/2, p-LATS1, and p-YAP decreased, <i>P</i> &lt; 0.05, and YAP translocated to the nucleus), thereby activating Müller cells (expression of marker proteins GS and Kir4.1 decreased, while expression of GFAP, AQP4, and inflammatory mediators IL-1β, IL-6, VEGF increased, <i>P</i> &lt; 0.05). Key rescue experiments demonstrated that Drp1 silencing (reduced p-Drp1 level, <i>P</i> &lt; 0.05) reversed the aforementioned activation; however, co-administration of the Hippo pathway inhibitor XMU-MP-1 re-induced cell activation, proving that the Hippo pathway is a necessary downstream mediator of mitochondrial fission. In a diabetic rat model, elevated p-Drp1, Hippo pathway inhibition, and cell activation were similarly observed; the mitochondrial fission inhibitor Mdivi-1 alleviated this pathological process, whereas XMU-MP-1 counteracted its protective effects. This study systematically elucidates, from ex vivo to in vivo, the causal regulatory axis of “HG- mitochondrial fission- Hippo pathway inhibition—Müller cell activation,” providing experimental evidence and a potential target for developing DR-targeted therapeutic strategies centered on intervening in mitochondrial dynamics.</p>

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High glucose-induced mitochondrial fission promotes Müller cell activation via suppression of the Hippo pathway

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Bo Li,
  • Xing Wang,
  • Xiao-li Hao,
  • Qin Wang,
  • Bing Xu,
  • Hui Peng,
  • Peng Wang

摘要

Diabetic retinopathy (DR) is the leading cause of blindness in diabetic patients, in which high glucose (HG)-induced Müller cell activation constitutes a central pathological event. This study aimed to untangle the critical role and mechanism of mitochondrial fission in this process. We found that under HG conditions, the level of p-Drp1 was significantly elevated (P < 0.05), driving excessive mitochondrial fission. Functional experiments confirmed that artificially enhancing mitochondrial fission directly inhibited the Hippo signaling pathway (levels of core proteins p-MST1/2, p-LATS1, and p-YAP decreased, P < 0.05, and YAP translocated to the nucleus), thereby activating Müller cells (expression of marker proteins GS and Kir4.1 decreased, while expression of GFAP, AQP4, and inflammatory mediators IL-1β, IL-6, VEGF increased, P < 0.05). Key rescue experiments demonstrated that Drp1 silencing (reduced p-Drp1 level, P < 0.05) reversed the aforementioned activation; however, co-administration of the Hippo pathway inhibitor XMU-MP-1 re-induced cell activation, proving that the Hippo pathway is a necessary downstream mediator of mitochondrial fission. In a diabetic rat model, elevated p-Drp1, Hippo pathway inhibition, and cell activation were similarly observed; the mitochondrial fission inhibitor Mdivi-1 alleviated this pathological process, whereas XMU-MP-1 counteracted its protective effects. This study systematically elucidates, from ex vivo to in vivo, the causal regulatory axis of “HG- mitochondrial fission- Hippo pathway inhibition—Müller cell activation,” providing experimental evidence and a potential target for developing DR-targeted therapeutic strategies centered on intervening in mitochondrial dynamics.