Peroxisome proliferator-activated receptor-gamma dependent pathway reduces the phosphorylation of dynamin-related protein 1 and ameliorates hippocampal injury induced by global ischemia in rats.

Yao-Chung Chuang,Tsu-Kung Lin,Chia-Wei Liou,Shang-Der Chen,Jenq-Lin Yang,Ding-I Yang

doi:10.1186/s12929-016-0262-3

Abstract

BackgroundDynamin-related protein 1 (Drp1) is a mitochondrial fission protein that, upon phosphorylation at serine 616 (p-Drp1(Ser616)), plays a pivotal role in neuronal death after ischemia. In the present study, we hypothesized that peroxisome proliferator-activated receptor-gamma (PPARγ)-dependent pathway can reduce the expression of p-Drp1(Ser616) and ameliorate hippocampal injury induced by global ischemia in rats.ResultsWe found that pretreatment of the rats with Mdivi-1, a selective Drp1 inhibitor, decreased the level of transient global ischemia (TGI)-induced p-Drp1(Ser616) and reduced cellular contents of oxidized proteins, activated caspase-3 expression as well as the extent of DNA fragmentation. Delivery of siRNA against Drp1 attenuated the expression of p-Drp1(Ser616) that was accompanied by alleviation of the TGI-induced protein oxidation, activated caspase-3 expression and DNA fragmentation in hippocampal proteins. Exogenous application of pioglitazone, a PPARγ agonist, reduced the p-Drp1(Ser616) expression, decreased TGI-induced oxidative stress and activated caspase-3 expression, lessened the extents of DNA fragmentation, and diminished the numbers of TUNEL-positive neuronal cells; all of these effects were reversed by GW9662, a PPARγ antagonist.ConclusionsOur findings thus indicated that inhibition of TGI-induced p-Drp1(Ser616) expression by Drp1 inhibitor and Drp1-siRNA can decrease protein oxidation, activated caspase-3 expression and neuronal damage in the hippocampal CA1 subfield. PPARγ agonist, through PPARγ-dependent mechanism and via decreasing p-Drp1(Ser616) expression, can exert anti-oxidative and anti-apoptotic effects against ischemic neuronal injury.

Highlights

Dynamin-related protein 1 (Drp1) is a mitochondrial fission protein that, upon phosphorylation at serine 616 (p-Drp1(Ser616)), plays a pivotal role in neuronal death after ischemia
The results demonstrate that transient global ischemia (TGI) increases p-Drp1(Ser616) expression, a phosphorylation site important for increasing mitochondrial fission, in the hippocampal CA1 subfield after TGI
peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, pioglitazone, reduced the p-Drp1(Ser616) expression, decreased TGI-induced oxidative stress, lessened the extents of DNA fragmentation, and diminished the numbers of transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive neuronal cells; all of these effects were reversed by GW9662, a PPARγ antagonist

Summary

Introduction

Dynamin-related protein 1 (Drp1) is a mitochondrial fission protein that, upon phosphorylation at serine 616 (p-Drp1(Ser616)), plays a pivotal role in neuronal death after ischemia. Mitochondria are dynamic organelles that maintain their shape or morphology via two opposing processes: fission and fusion [4,5,6]. Just before the apoptotic processes, mitochondria fragment into multiple small units (fission) and blocking mitochondrial fission can inhibit cytochrome c release with delayed cell death [2]. An important fission protein, plays a crucial role in focal cerebral ischemia and inhibition of Drp can reduce the infarct volumes [7,8,9]. Expression of the dominantnegative Drp mutant in cell lines decreases mitochondrial fragmentation and blocks cell death in response to various apoptotic insults [10, 11]

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