Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells

Yabin Gong; Ning Tang; Panrao Liu; Yingjie Sun; Shanxin Lu; Weiwei Liu; Lei Tan; Cuiping Song; Xusheng Qiu; Ying Liao; Shengqing Yu; Xiufan Liu; Shu-Hai Lin; Chan Ding

doi:10.1080/15548627.2021.1990515

Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells

Autophagy. 2022 Jul;18(7):1503-1521. doi: 10.1080/15548627.2021.1990515. Epub 2021 Oct 31.

Authors

Yabin Gong¹, Ning Tang^{1

2}, Panrao Liu^{1

3}, Yingjie Sun¹, Shanxin Lu⁴, Weiwei Liu¹, Lei Tan¹, Cuiping Song¹, Xusheng Qiu¹, Ying Liao¹, Shengqing Yu¹, Xiufan Liu³, Shu-Hai Lin⁴, Chan Ding^{1

3}

Affiliations

¹ Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P.R. China.
² College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi, China.
³ Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, P.R. China.
⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, P.R. China.

Abstract

Lacking a self-contained metabolism network, viruses have evolved multiple mechanisms for rewiring the metabolic system of their host to hijack the host's metabolic resources for replication. Newcastle disease virus (NDV) is a paramyxovirus, as an oncolytic virus currently being developed for cancer treatment. However, how NDV alters cellular metabolism is still far from fully understood. In this study, we show that NDV infection reprograms cell metabolism by increasing glucose utilization in the glycolytic pathway. Mechanistically, NDV induces mitochondrial damage, elevated mitochondrial reactive oxygen species (mROS) and ETC dysfunction. Infection of cells depletes nucleotide triphosphate levels, resulting in elevated AMP:ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and MTOR crosstalk mediated autophagy. In a time-dependent manner, NDV shifts the balance of mitochondrial dynamics from fusion to fission. Subsequently, PINK1-PRKN-dependent mitophagy was activated, forming a ubiquitin chain with MFN2 (mitofusin 2), and molecular receptor SQSTM1/p62 recognized damaged mitochondria. We also found that NDV infection induces NAD⁺-dependent deacetylase SIRT3 loss via mitophagy to engender HIF1A stabilization, leading to the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Overall, these studies support a model that NDV modulates host cell metabolism through PINK1-PRKN-dependent mitophagy for degrading SIRT3.Abbreviations: AMPK: AMP-activated protein kinase; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECAR: extracellular acidification rate; hpi: hours post infection LC-MS: liquid chromatography-mass spectrometry; mito-QC: mCherry-GFP-FIS1[mt101-152]; MFN2: mitofusin 2; MMP: mitochondrial membrane potential; mROS: mitochondrial reactive oxygen species; MOI: multiplicity of infection; 2-NBDG: 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose; NDV: newcastle disease virus; OCR: oxygen consumption rate; siRNA: small interfering RNA; SIRT3: sirtuin 3; TCA: tricarboxylic acid; TCID₅₀: tissue culture infective doses.

Keywords: Cellular metabolism; SIRT3; glycolysis; mitochondrial fission; mitophagy; newcastle disease virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Autophagy
Energy Metabolism
Mitophagy* / genetics
Newcastle disease virus / metabolism
Reactive Oxygen Species / metabolism
Sirtuin 3* / metabolism
Ubiquitin-Protein Ligases / metabolism

Substances

Reactive Oxygen Species
Ubiquitin-Protein Ligases
AMP-Activated Protein Kinases
Sirtuin 3

Grants and funding

This work was supported by the National Natural Science Foundation of China [32030108]; National Natural Science Foundation of China [91957120]; National Natural Science Foundation of China [32122085]; Natural Science Foundation of Shanghai [18ZR1448700].