Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P.R. China.
College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi, China.
Autophagy. 2022 Jul;18(7):1503-1521. doi: 10.1080/15548627.2021.1990515. Epub 2021 Oct 31.
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. 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; TCID: tissue culture infective doses.
新城疫病毒（NDV）是一种副粘病毒，作为一种正在开发用于癌症治疗的溶瘤病毒。然而，NDV 如何改变细胞代谢仍远未完全了解。在这项研究中，我们表明 NDV 通过增加糖酵解途径中的葡萄糖利用来重新编程细胞代谢。在机制上，NDV 诱导线粒体损伤、升高的线粒体活性氧（mROS）和 ETC 功能障碍。细胞感染会耗尽核苷酸三磷酸水平，导致 AMP：ATP 比值升高、AMP 激活的蛋白激酶（AMPK）磷酸化和 MTOR 串扰介导的自噬。随着时间的推移，NDV 将线粒体动力学的平衡从融合转变为裂变。随后，PINK1-PRKN 依赖性线粒体自噬被激活，与 MFN2（线粒体融合蛋白 2）形成泛素链，分子受体 SQSTM1/p62 识别受损的线粒体。我们还发现，NDV 感染通过线粒体自噬诱导 NAD 依赖性去乙酰化酶 SIRT3 丧失，导致 HIF1A 稳定，从而导致从氧化磷酸化（OXPHOS）切换到有氧糖酵解。总的来说，这些研究支持了一种模型，即 NDV 通过 PINK1-PRKN 依赖性线粒体自噬来调节宿主细胞代谢，从而降解 SIRT3。AMPK：AMP 激活的蛋白激酶；CCCP：羰基氰化物 3-氯苯腙；ECAR：细胞外酸化率；hpi：感染后小时；LC-MS：液相色谱-质谱；mito-QC：mCherry-GFP-FIS1[mt101-152]；MFN2：线粒体融合蛋白 2；MMP：线粒体膜电位；mROS：线粒体活性氧；MOI：感染复数；2-NBDG：2-（N-（7-硝基苯并-2-氧代-1,3-二唑-4-基）氨基）-2-脱氧葡萄糖；NDV：新城疫病毒；OCR：耗氧量；siRNA：小干扰 RNA；SIRT3：Sirtuin 3；TCA：三羧酸；TCID：组织培养感染剂量。
