Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: effects which contribute to the development of diabetic encephalopathy

J Neuroinflammation. 2025 Apr 18;22(1):111. doi: 10.1186/s12974-025-03441-3.

Shan Huang ^# ¹, Mengyu Hua ^# ¹, Wei Liu ², Ziyun Zhuang ¹ ³, Xiaolin Han ¹, Xiaochen Zhang ¹ ⁴, Zhonghao Liang ¹, Xiaojing Liu ¹ ⁵, Nengjun Lou ¹ ⁵, Shuyan Yu ⁶, Shihong Chen ⁷ ⁸, Xianghua Zhuang ⁹ ¹⁰

Affiliations

1 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China.
2 Rehabilitation Hospital, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, China.
3 Department of Endocrinology and Metabolism, The First People's Hospital of Jinan, Jinan, 250011, China.
4 Department of Clinical Medicine, Heze Medical College, Heze, 274009, China.
5 Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan, 250033, China.
6 Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China. shuyanyu@sdu.edu.cn.
7 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China. chenshihong@sdu.edu.cn.
8 Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan, 250033, China. chenshihong@sdu.edu.cn.
9 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China. zhuangxianghua@email.sdu.edu.cn.
10 Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan, 250033, China. zhuangxianghua@email.sdu.edu.cn.
# Contributed equally.

PMID: 40251630 DOI: 10.1186/s12974-025-03441-3

Abstract

Diabetic encephalopathy (DE) is a common, chronic central nervous system complication of diabetes mellitus, and represents a condition without a clear pathogenesis or effective therapy. Findings from recent studies have indicated that a dyshomeostasis of mitochondria-associated endoplasmic reticulum membranes (MAMs) may be involved in the development of neurodegenerative diseases such as DE. MAMs represent a dynamic contact site between mitochondrial and endoplasmic reticulum (ER) membranes, where phospholipid components are exchanged with each Other. Previous work within our laboratory has revealed that Lipin1, a critical enzyme related to phospholipid synthesis, is involved in the pathogenesis of DE. Here, we show that Lipin1 is downregulated within the hippocampus of a DE mouse model, an effect which was accompanied with a decrease in MAMs. Knockdown of Lipin1 in the hippocampus of normal mice resulted in a reduction of MAMs, ER stress, abnormal mitochondrial function, as well as impaired synaptic plasticity and cognitive function. These same phenomena were observed in the DE model, while an upregulation of Lipin1 within the hippocampus of DE mice improved these symptoms. Low levels of Lipin1 in DE mice were also associated with neuroinflammation, while an overexpression of Lipin1 significantly ameliorated the neuroinflammation observed in DE mice. In conclusion, Lipin1 ameliorates pathological changes associated with DE in a mouse model via prevention of dyshomeostasis in MAMs. Such findings suggest that Lipin1 may be serve as a new potential target for the treatment of DE.

Keywords

Cognitive dysfunction; Diabetic encephalopathy; Lipin1; MAMs; Mitochondria.

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