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Background <p>Mitochondrial structural abnormalities and impaired energy metabolism are recognized hallmarks of diabetic cardiomyopathy (DCM). GULP1 (PTB-domain engulfment adapter protein 1, also known as CED-6) is a cytoplasmic adaptor protein containing a phosphotyrosine-binding domain. GULP1 has been implicated in metabolic disorders, particularly in type 2 diabetes. However, its potential involvement in cardiovascular homeostasis remains unclear. This study aimed to investigate whether GULP1 attenuates DCM by preserving mitochondrial architecture and bioenergetic function, and to explore the underlying molecular mechanisms.</p> Methods <p>Cardiac-specific Gulp1 knockout (Gulp1<sup>KO</sup>) and overexpressing (Gulp1<sup>KI</sup>) mice, along with their wild-type littermates (Gulp1<sup>f/f</sup>, Gulp1<sup>WT</sup>), were fed a high-fat diet for 6 months to induce DCM. Cardiac function was assessed by echocardiography and hemodynamic measurements. Cardiac mitochondrial structure and function were evaluated using electron microscopy, enzyme activity assays, ATP production and fatty acid oxidation. Primary ventricular myocytes derived from neonatal and adult mice were employed to delineate the molecular and signaling mechanisms underlying GULP1-mediated protection against palmitic acid (PA)-induced mitochondrial morphological alterations and dysfunction.</p> Results <p>GULP1 expression was markedly reduced in myocardial tissues from DCM patients and mouse models. Cardiac-specific GULP1 overexpression significantly attenuated cardiac dysfunction, alleviated mitochondrial structural disruption and respiratory impairment in diabetes, while reducing oxidative stress and cardiomyocyte apoptosis. Mechanistically, GULP1 directly interacted with IKIP (inhibitor of nuclear factor κB kinase-interacting protein) to alleviate IKIP-mediated inhibition of IKKβ-dependent NF-κB activation. This interaction enhanced NF-κB signaling, upregulated OPA1 (optic atrophy 1) expression and restored mitochondrial morphology, while improving fatty acid metabolism in DCM hearts. Consistently, GULP1 prevented PA-induced mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis in vitro through the IKIP/NF-κB/OPA1 signaling axis.</p> Conclusions <p>The IKIP/NF-κB/OPA1 signaling axis constitutes an essential mechanism through which GULP1 preserves mitochondrial morphofunction, thereby translating into cardioprotection against diabetic cardiomyopathy. These results identify GULP1 as a compelling therapeutic target for DCM. </p>

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GULP1 protects against diabetic cardiomyopathy through IKIP/NF-κB-dependent improvement of mitochondrial function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Meng-Yuan Jiang,
  • Xiao-Hua Zhang,
  • Huan-Le Zhang,
  • Yue Hou,
  • Mei-Ying Qi,
  • Yi-Xuan Zuo,
  • Chuang Sun,
  • Xin-Chun Dai,
  • Ning-Ning Zhang,
  • Tian-Qi Chen,
  • Yan Zhang,
  • Wan-Rong Man,
  • Cong-Ye Li,
  • Jie Lin,
  • Wen Ge,
  • Li-Yu Yang,
  • Xing Qin,
  • Dong-Dong Sun

摘要

Background

Mitochondrial structural abnormalities and impaired energy metabolism are recognized hallmarks of diabetic cardiomyopathy (DCM). GULP1 (PTB-domain engulfment adapter protein 1, also known as CED-6) is a cytoplasmic adaptor protein containing a phosphotyrosine-binding domain. GULP1 has been implicated in metabolic disorders, particularly in type 2 diabetes. However, its potential involvement in cardiovascular homeostasis remains unclear. This study aimed to investigate whether GULP1 attenuates DCM by preserving mitochondrial architecture and bioenergetic function, and to explore the underlying molecular mechanisms.

Methods

Cardiac-specific Gulp1 knockout (Gulp1KO) and overexpressing (Gulp1KI) mice, along with their wild-type littermates (Gulp1f/f, Gulp1WT), were fed a high-fat diet for 6 months to induce DCM. Cardiac function was assessed by echocardiography and hemodynamic measurements. Cardiac mitochondrial structure and function were evaluated using electron microscopy, enzyme activity assays, ATP production and fatty acid oxidation. Primary ventricular myocytes derived from neonatal and adult mice were employed to delineate the molecular and signaling mechanisms underlying GULP1-mediated protection against palmitic acid (PA)-induced mitochondrial morphological alterations and dysfunction.

Results

GULP1 expression was markedly reduced in myocardial tissues from DCM patients and mouse models. Cardiac-specific GULP1 overexpression significantly attenuated cardiac dysfunction, alleviated mitochondrial structural disruption and respiratory impairment in diabetes, while reducing oxidative stress and cardiomyocyte apoptosis. Mechanistically, GULP1 directly interacted with IKIP (inhibitor of nuclear factor κB kinase-interacting protein) to alleviate IKIP-mediated inhibition of IKKβ-dependent NF-κB activation. This interaction enhanced NF-κB signaling, upregulated OPA1 (optic atrophy 1) expression and restored mitochondrial morphology, while improving fatty acid metabolism in DCM hearts. Consistently, GULP1 prevented PA-induced mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis in vitro through the IKIP/NF-κB/OPA1 signaling axis.

Conclusions

The IKIP/NF-κB/OPA1 signaling axis constitutes an essential mechanism through which GULP1 preserves mitochondrial morphofunction, thereby translating into cardioprotection against diabetic cardiomyopathy. These results identify GULP1 as a compelling therapeutic target for DCM.