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Background <p>Diabetic cardiomyopathy (DCM) involves cardiac dysfunction/remodeling with mitochondrial stress and impaired mitochondrial proteostasis. The role of dual-specificity phosphatases (DUSPs) in these processes remains unclear. We examined whether Dusp15 modulates diabetic cardiac injury and whether mtHsp70/mito-UPR-linked proteostasis is involved.</p> Methods <p>DCM was induced in mice by high-fat diet (HFD) combined with low-dose streptozotocin (STZ). We studied cardiomyocyte-specific <i>Dusp15</i> knockout <i>(Dusp15</i><sup><i>Cko</i></sup>) mice, a <i>Dusp15</i> gain-of-function line, and high-glucose-treated HL-1 cardiomyocytes. Cardiac function/remodeling were assessed by echocardiography and molecular/histological analyses. Dusp15-mtHsp70 signaling was interrogated by protein interaction assays and mtHsp70 <i>Thr116</i> genetic models.</p> Results <p>Dusp15 was reduced in diabetic hearts and associated with impaired contractility. Dusp15 gain-of-function improved cardiac function and reduced remodeling/inflammation, whereas <i>Dusp15</i><sup><i>Cko</i></sup> worsened diabetic injury, indicating a cardiomyocyte-necessary role for Dusp15. Dusp15 associated with mtHsp70 and supported mtHsp70-linked mitochondrial proteostasis/mito-UPR in cardiomyocytes. Genetically, <i>mtHsp70</i><sup><i>T116A</i></sup> knock-in mice were substantially protected from diabetic cardiac dysfunction/remodeling. Finally, dapagliflozin (DAPA) improved diabetic cardiac outcomes, and its benefit was reduced in <i>Dusp15</i><sup><i>Cko</i></sup> mice, suggesting Dusp15 as an important mediator.</p> Conclusion <p>Dusp15 is a stress-responsive regulator that protects against diabetic cardiac dysfunction and remodeling through mtHsp70-associated mito-UPR signaling. Targeting the Dusp15–mtHsp70 axis may represent a therapeutic strategy for diabetic cardiomyopathy.</p>

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Dusp15 modulates mtHsp70 Thr116 phosphorylation state to preserve mito-UPR and attenuate cardiac dysfunction in diabetic cardiomyopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Yan Liu,
  • Hongshuo Shi,
  • Chun Li,
  • Haowen Zhuang,
  • Yinglong Li,
  • Xiuling He,
  • Ying Jiang,
  • Zhiyu Jin,
  • Zhijiang Guo,
  • Sangbing Ong,
  • Yuanyuan Wang,
  • Xing Chang,
  • Guipeng An,
  • Junyan Wang

摘要

Background

Diabetic cardiomyopathy (DCM) involves cardiac dysfunction/remodeling with mitochondrial stress and impaired mitochondrial proteostasis. The role of dual-specificity phosphatases (DUSPs) in these processes remains unclear. We examined whether Dusp15 modulates diabetic cardiac injury and whether mtHsp70/mito-UPR-linked proteostasis is involved.

Methods

DCM was induced in mice by high-fat diet (HFD) combined with low-dose streptozotocin (STZ). We studied cardiomyocyte-specific Dusp15 knockout (Dusp15Cko) mice, a Dusp15 gain-of-function line, and high-glucose-treated HL-1 cardiomyocytes. Cardiac function/remodeling were assessed by echocardiography and molecular/histological analyses. Dusp15-mtHsp70 signaling was interrogated by protein interaction assays and mtHsp70 Thr116 genetic models.

Results

Dusp15 was reduced in diabetic hearts and associated with impaired contractility. Dusp15 gain-of-function improved cardiac function and reduced remodeling/inflammation, whereas Dusp15Cko worsened diabetic injury, indicating a cardiomyocyte-necessary role for Dusp15. Dusp15 associated with mtHsp70 and supported mtHsp70-linked mitochondrial proteostasis/mito-UPR in cardiomyocytes. Genetically, mtHsp70T116A knock-in mice were substantially protected from diabetic cardiac dysfunction/remodeling. Finally, dapagliflozin (DAPA) improved diabetic cardiac outcomes, and its benefit was reduced in Dusp15Cko mice, suggesting Dusp15 as an important mediator.

Conclusion

Dusp15 is a stress-responsive regulator that protects against diabetic cardiac dysfunction and remodeling through mtHsp70-associated mito-UPR signaling. Targeting the Dusp15–mtHsp70 axis may represent a therapeutic strategy for diabetic cardiomyopathy.