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

Jiaxiu Li; Ya Hui; Zhiqiang Xu; Jie Tan; Kai Yin; Liuyu Kuang; Yunyun Tang; Junjie Wei; Qiongsui Zhong; Tianpeng Zheng

doi:10.1016/j.isci.2023.106271

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. eCollection 2023 Mar 17.

Authors

Jiaxiu Li^{1

2

3}, Ya Hui^{1

2}, Zhiqiang Xu^{1

2}, Jie Tan³, Kai Yin², Liuyu Kuang^{1

2}, Yunyun Tang^{1

2}, Junjie Wei⁴, Qiongsui Zhong⁴, Tianpeng Zheng^{1

2

3

5}

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.

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.