OPA1 overexpression ameliorates mitochondrial cristae remodeling, mitochondrial dysfunction, and neuronal apoptosis in prion diseases

Wei Wu,Dongming Yang,Deming Zhao,Jian Qiao,Jie Li,Lifeng Yang,Zhiling Guan,Hongli Gao,Xiaoqian Wu,Wen Li,Syed Zahid Ali Shah,Mengyu Lai,Huafen Zhao,Xiangmei Zhou,Xixi Zhang

doi:10.1038/s41419-019-1953-y

Wei Wu, Dongming Yang + Show 13 more

Open Access

https://doi.org/10.1038/s41419-019-1953-y

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Abstract

Prion diseases caused by the cellular prion protein (PrPC) conversion into a misfolded isoform (PrPSc) are associated with multiple mitochondrial damages. We previously reported mitochondrial dynamic abnormalities and cell death in prion diseases via modulation of a variety of factors. Optic atrophy 1 (OPA1) is one of the factors that control mitochondrial fusion, mitochondrial DNA (mtDNA) maintenance, bioenergetics, and cristae integrity. In this study, we observed downregulation of OPA1 in prion disease models in vitro and in vivo, mitochondria structure damage and dysfunction, loss of mtDNA, and neuronal apoptosis. Similar mitochondria findings were seen in OPA1-silenced un-infected primary neurons. Overexpression of OPA1 not only alleviated prion-induced mitochondrial network fragmentation and mtDNA loss, decrease in intracellular ATP, increase in ADP/ATP ratio, and decrease in mitochondrial membrane potential but also protected neurons from apoptosis by suppressing the release of cytochrome c from mitochondria to cytosol and activation of the apoptotic factor, caspase 3. Our results demonstrated that overexpression of OPA1 alleviates prion-associated mitochondrial network fragmentation and cristae remodeling, mitochondrial dysfunction, mtDNA depletion, and neuronal apoptosis, suggesting that OPA1 may be a novel and effective therapeutic target for prion diseases.

Highlights

Prion diseases are transmissible fatal neurodegenerative disorders, which occur in humans (e.g., Creutzfeldt–Jakob Disease [CJD], Kuru, and so on) and other mammalian species[1]
Our research shows that the protein level of Optic atrophy 1 (OPA1) is dramatically downregulated in in vitro and in vivo models of prion diseases, and OPA1 overexpression alleviated PrP106–126-induced mitochondrial cristae collapse, mitochondrial DNA (mtDNA) depletion, mitochondrial dysfunction, and neuronal apoptosis
OPA1 is downregulated in prion disease models in vivo and in vitro

Summary

Introduction

Prion diseases are transmissible fatal neurodegenerative disorders, which occur in humans (e.g., Creutzfeldt–Jakob Disease [CJD], Kuru, and so on) and other mammalian species (bovine spongiform encephalopathy [BSE] in cattle, scrapie in sheep, chronic wasting disease [CWD] in cervidae)[1]. Mitochondrial damage and dysfunction is a common feature in prion diseases and other neurodegenerative conditions. Abnormalities of mitochondrial dynamics occur in the early stage of neurodegenerative diseases[8]. Wu et al Cell Death and Disease (2019)10:710 protein machinery that controls mitochondrial dynamics is a set of large dynamin-related GTPase proteins. The dynamin-like protein 1 (DLP1) is a key player in mitochondria fission process; during fission, cytosolic DLP1 translocates to mitochondrial outer membrane by receptor proteins, such as fission 1 (Fis 1) and mitochondria fission factor (Mff)[11,12,13]. The mitofusins 1/2 (MNF1 and MFN2) are required for fusion of the outer mitochondrial membrane; MFN2 is considered to play a major regulatory role and MFN1 tethers two juxtaposed organelle[14,15]. OPA1 controls apoptosis through cristae remodeling and cytochrome c release independently from mitochondrial fusion[19,20]

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