2. Academic Validation
  3. Non-canonical function of DPP4 promotes cognitive impairment through ERp29-associated mitochondrial calcium overload in diabetes

Non-canonical function of DPP4 promotes cognitive impairment through ERp29-associated mitochondrial calcium overload in diabetes

  • iScience. 2023 Feb 27;26(3):106271. doi: 10.1016/j.isci.2023.106271.
Jiaxiu Li 1 2 3,  Ya Hui 1 2,  Zhiqiang Xu 1 2,  Jie Tan 3,  Kai Yin 2,  Liuyu Kuang 1 2,  Yunyun Tang 1 2,  Junjie Wei 4,  Qiongsui Zhong 4,  Tianpeng Zheng 1 2 3 5
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China.
  • 2 Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China.
  • 3 Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, P. R. China.
  • 4 Lingui Clinical Medical College, Guilin Medical University, Guilin, Guangxi 541199, P. R. China.
  • 5 Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China.
PMID: 36936785 DOI: 10.1016/j.isci.2023.106271
Abstract

DPP4 has been shown to induce diabetes-associated mitochondrial dysfunction and cognitive impairment through its non-canonical function. Here, we report that enhanced DPP4 expression in diabetes contributes to IP3R2-mediated mitochondria-associated ER membrane (MAM) formation, mitochondria calcium overload, and cognitive impairment, and its knockdown showed opposite effects. Mechanistically, DPP4 binds to PAR2 in hippocampal neurons and activates ERK1/2/CEBPB signaling, which upregulates ERp29 expression and promotes its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting MAM formation, mitochondria calcium overload, and cognitive impairment. Meanwhile, targeting DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling achieved satisfactory therapeutic effects on MAM formation, mitochondria calcium overload, and cognitive impairment. Notably, DPP4 activates this pathway in an enzymatic activity-independent manner, suggesting the non-canonical role of DPP4 in the pathogenesis of mitochondria calcium overload and cognitive impairment in diabetes. Together, these results identify DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling as a promising therapeutic target for the treatment of cognitive impairment in type 2 diabetes.

Keywords

Biological sciences; Cell biology; Molecular biology; Physiology.

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