Phosphatidate phosphatase Lipin1 involves in diabetic encephalopathy pathogenesis via regulating synaptic mitochondrial dynamics
Xiaolin Han,
Shan Huang,
Ziyun Zhuang,
Xiaochen Zhang,
Min Xie,
Nengjun Lou,
Mengyu Hua,
Xianghua Zhuang,
Shuyan Yu,
Shihong Chen
Affiliations
Xiaolin Han
Depratment of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China
Shan Huang
Depratment of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China
Ziyun Zhuang
Depratment of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China; Department of Endocrinology and Metabolism, First People’s Hospital of Jinan, Jinan, 250011, China
Xiaochen Zhang
Depratment of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China; Department of Clinical Medicine, Heze Medical College, Heze, 274009, China
Min Xie
Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, 256603, China
Nengjun Lou
Depratment 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
Mengyu Hua
Depratment of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, 250033, China
Xianghua Zhuang
Depratment 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; Corresponding author. The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, China.
Shuyan Yu
Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China; Corresponding author. Shandong University, 44 Wenhua West Road, Jinan, 250012, China.
Shihong Chen
Depratment 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; Corresponding author. The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, China.
Diabetic encephalopathy (DE) is a common central nervous system complication of diabetes mellitus without effective therapy currently. Recent studies have highlighted synaptic mitochondrial damages as a possible pathological basis for DE, but the underlying mechanisms remain unclear. Our previous work has revealed that phosphatidate phosphatase Lipin1, a critical enzyme involved with phospholipid synthesis, is closely related to the pathogenesis of DE. Here, we demonstrate that Lipin1 is significantly down-regulated in rat hippocampus of DE. Knock-down of Lipin1 within hippocampus of normal rats induces dysregulation of homeostasis in synaptic mitochondrial dynamics with an increase of mitochondrial fission and a decrease of fusion, then causes synaptic mitochondrial dysfunction, synaptic plasticity deficits as well as cognitive impairments, similar to that observed in response to chronic hyperglycemia exposure. In contrast, an up-regulation of Lipin1 within hippocampus in the DE model ameliorates this cascade of dysfunction. We also find that the effect of Lipin1 that regulating mitochondrial dynamics results from maintaining appropriate phospholipid components in the mitochondrial membrane. In conclusion, alterations in hippocampal Lipin1 contribute to hippocampal synaptic mitochondrial dysfunction and cognitive deficits observed in DE. Targeting Lipin1 might be a potential therapeutic strategy for the clinical treatment of DE.
