2. Academic Validation
  3. Lipin1 ameliorates cognitive ability of diabetic encephalopathy via regulating Ca2+ transfer through mitochondria-associated endoplasmic reticulum membranes

Lipin1 ameliorates cognitive ability of diabetic encephalopathy via regulating Ca2+ transfer through mitochondria-associated endoplasmic reticulum membranes

  • Int Immunopharmacol. 2025 Mar 26:150:114266. doi: 10.1016/j.intimp.2025.114266.
Ziyun Zhuang 1,  Shan Huang 2,  Xiaochen Zhang 3,  Xiaolin Han 2,  Mengyu Hua 2,  Zhonghao Liang 2,  Nengjun Lou 4,  Li Lv 4,  Fengjie Zheng 4,  Liang Zhang 4,  Xiaojing Liu 5,  Shuyan Yu 6,  Shihong Chen 7,  Xianghua Zhuang 8
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Department of Endocrinology and Metabolism, The First People's Hospital of Jinan, Jinan 250011, China.
  • 2 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China.
  • 3 Department of Clinical Medicine, Heze Medical College, Heze 274009, China.
  • 4 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan 250033, China.
  • 5 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China. Electronic address: liuxiaojingqingyi@163.com.
  • 6 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Department of Physiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address: shuyanyu@sdu.edu.cn.
  • 7 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan 250033, China. Electronic address: chenshihong@sdu.edu.cn.
  • 8 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan 250033, China. Electronic address: zhuangxianghua@email.sdu.edu.cn.
PMID: 39961213 DOI: 10.1016/j.intimp.2025.114266
Abstract

Diabetic encephalopathy (DE) is a common central nervous system complication resulting from diabetes mellitus (DM). While the exact pathogenesis remains unclear, a homeostatic imbalance of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) within neurons has been shown to be closely associated with the dysfunctional cognitive pathology of this condition. Our previous work has revealed that phosphatidate Phosphatase Lipin1 plays a critical role in the cognitive processes of DE via regulating mitochondrial function. In this study, we reported that the integrity of neuronal MAMs was disrupted in DE mice, which was accompanied by a decrease in the expression of hippocampal Lipin1. With a knock-down of hippocampal Lipin1 in normal mice, ER stress was induced, MAMs structures were impaired and CA2+ transfer was suppressed. Such effects resulted in mitochondrial dysfunction, synaptic plasticity impairments, and finally cognitive dysfunctions. In contrast, an up-regulation of hippocampal Lipin1 in the DE model partially alleviated these dysfunctions. These results suggest that Lipin1 may ameliorate the cognitive dysfunctions associated with DE via regulating CA2+ transfers through MAMs. Therefore, targeting Lipin1 may serve as a therapeutic strategy for the clinical treatment of DE.

Keywords

Ca(2+) transfer; Cognitive dysfunction; Diabetic encephalopathy; Lipin1; Mitochondria-associated endoplasmic reticulum membranes.

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