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

Jiaxiu Li1,2,3, Ya Hui1,2, Zhiqiang Xu1,2

  • 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China.

Iscience
|March 20, 2023
PubMed

Insights

Dipeptidyl peptidase-4 (DPP4) exacerbates cognitive impairment in diabetes by promoting mitochondrial dysfunction via ERp29 and IP3R2 interactions. Targeting this DPP4-PAR2 pathway offers a novel therapeutic strategy for diabetic cognitive deficits.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Endocrinology

Background:

  • Dipeptidyl peptidase-4 (DPP4) is implicated in diabetes-associated mitochondrial dysfunction and cognitive impairment.
  • Its non-canonical functions, beyond glucose metabolism, are increasingly recognized in disease pathogenesis.

Purpose of the Study:

  • To elucidate the mechanism by which enhanced DPP4 expression contributes to cognitive impairment in diabetes.
  • To investigate the role of DPP4 in mitochondria-associated ER membrane (MAM) formation and mitochondrial calcium overload.
  • To evaluate the therapeutic potential of targeting the DPP4 signaling pathway.

Main Methods:

  • Investigated DPP4 expression and its effects on IP3R2-mediated MAM formation and mitochondrial calcium levels in a diabetic model.
  • Utilized molecular biology techniques to identify signaling pathways involved in DPP4-induced cognitive impairment, including PAR2, ERK1/2, CEBPB, and ERp29.
  • Assessed the therapeutic efficacy of targeting the DPP4-mediated signaling cascade.

Main Results:

  • Enhanced DPP4 expression in diabetes promotes MAM formation, mitochondrial calcium overload, and cognitive impairment.
  • DPP4 binds to PAR2 in hippocampal neurons, activating ERK1/2/CEBPB signaling, upregulating ERp29, and inhibiting IP3R2 degradation.
  • Targeting the DPP4-PAR2/ERK1/2/CEBPB/ERp29 pathway demonstrated significant therapeutic benefits.
  • DPP4's action is independent of its enzymatic activity, highlighting a non-canonical role.

Conclusions:

  • DPP4 plays a critical role in diabetes-associated cognitive impairment through a non-canonical mechanism involving ERp29 and IP3R2.
  • The identified DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling pathway is a key driver of MAM formation and mitochondrial calcium dysregulation.
  • This pathway represents a promising therapeutic target for treating cognitive dysfunction in type 2 diabetes.
Keywords:
Biological sciencesCell biologyMolecular biologyPhysiology

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