Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus

Hyun Joo Shin,Dawon Kang,Hye Min Han,Gyeongah Park,Gu Seob Roh,Zhen Jin,Kyung Eun Kim,Hyun Joon Kim,Jong Youl Lee,Yong Chul Bae,Eun Ae Jeong,Hyeong Seok An,Jaewoong Lee

doi:10.1038/s41419-021-03723-7

Hyun Joo Shin, Dawon Kang + Show 11 more

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https://doi.org/10.1038/s41419-021-03723-7

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Abstract

Dynamin-related protein 1 (Drp1)-mediated mitochondrial dysfunction is associated with synaptic injury in the diabetic brain. However, the dysfunctional mitochondria by Drp1 deletion in the diabetic brain are poorly understood. Here, we investigated the effects of neuron-specific Drp1 deletion on synaptic damage and mitophagy in the hippocampus of a high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. HFD/STZ-induced diabetic mice exhibited metabolic disturbances and synaptic damages. Floxed Drp1 mice were crossed with Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα)-Cre mice, to generate neuron-specific Drp1 knockout (Drp1cKO) mice, which showed marked mitochondrial swelling and dendritic spine loss in hippocampal neurons. In particular, diabetic Drp1cKO mice exhibited an increase in dendritic spine loss and higher levels of oxidative stress and neuroinflammation compared with diabetic wild-type (WT) mice. Diabetic WT mice generally displayed increased Drp1-induced small mitochondrial morphology in hippocampal neurons, but large mitochondria were prominently observed in diabetic Drp1cKO mice. The levels of microtubule-associated protein 1 light-chain 3 and lysosomal-associated membrane protein 1 proteins were significantly increased in the hippocampus of diabetic Drp1cKO mice compared with diabetic WT mice. The inhibition of Drp1 adversely promotes synaptic injury and neurodegeneration in the diabetic brain. The findings suggest that the exploratory mechanisms behind Drp1-mediated mitochondrial dysfunction could provide a possible therapeutic target for diabetic brain complications.

Highlights

Introduction Type2 diabetes is a chronic disease that is characterized by low-grade chronic inflammation and insulin resistance, which result in hippocampal vulnerability and synaptic damage[1,2]
Immunofluorescence images revealed that Drp1 knockout (Drp1cKO) mice had mitochondrial marker or voltage-dependent anion channel 1 (VDAC1)-positive large perinuclear mitochondria, while calmodulindependent protein kinase IIα (CaMKIIα) Cre recombinase had no effect on perinuclear mitochondria morphology (Supplementary Fig. S1)
In the current study, we report that Drp[1] loss-mediated mitochondrial abnormalities promote synaptic damage in high-fat diet (HFD)/STZ-induced diabetic brain, which is especially susceptible to oxidative stress and neuroinflammation

Summary

Introduction

2 diabetes is a chronic disease that is characterized by low-grade chronic inflammation and insulin resistance, which result in hippocampal vulnerability and synaptic damage[1,2]. Many studies have reported that the diabetic brain exhibits neuroinflammation, synaptic injury, mitochondrial dysfunction, and defective autophagy[6,7,8]. An increase in Drp[1] protein expression is associated with pathophysiological events, such as diabetes, obesity, and neurodegenerative diseases[9,11,12,13,14]. Highglucose conditions can cause excessive mitochondrial fission and result in the increased production of reactive oxygen species (ROS) via mitochondrial hyperpolarization, Official journal of the Cell Death Differentiation Association

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