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孙连莲, 邵铱娜, 油梅香, 李成华. 2022: ROS介导的BNIP3依赖型线粒体自噬有助于灿烂弧菌感染下刺参(Apostichopus japonicus)体腔细胞的存活. 动物学研究, 43(2): 285-300. DOI: 10.24272/j.issn.2095-8137.2021.460
引用本文: 孙连莲, 邵铱娜, 油梅香, 李成华. 2022: ROS介导的BNIP3依赖型线粒体自噬有助于灿烂弧菌感染下刺参(Apostichopus japonicus)体腔细胞的存活. 动物学研究, 43(2): 285-300. DOI: 10.24272/j.issn.2095-8137.2021.460
Lian-Lian Sun, Yi-Na Shao, Mei-Xiang You, Cheng-Hua Li. 2022: ROS-mediated BNIP3-dependent mitophagy promotes coelomocyte survival in Apostichopus japonicus in response to Vibrio splendidus infection. Zoological Research, 43(2): 285-300. DOI: 10.24272/j.issn.2095-8137.2021.460
Citation: Lian-Lian Sun, Yi-Na Shao, Mei-Xiang You, Cheng-Hua Li. 2022: ROS-mediated BNIP3-dependent mitophagy promotes coelomocyte survival in Apostichopus japonicus in response to Vibrio splendidus infection. Zoological Research, 43(2): 285-300. DOI: 10.24272/j.issn.2095-8137.2021.460

ROS介导的BNIP3依赖型线粒体自噬有助于灿烂弧菌感染下刺参(Apostichopus japonicus)体腔细胞的存活

ROS-mediated BNIP3-dependent mitophagy promotes coelomocyte survival in Apostichopus japonicus in response to Vibrio splendidus infection

  • 摘要: 机体产生高水平的活性氧可以直接杀死病原体或作为信号分子诱导免疫反应发生,然而过量的活性氧会导致细胞死亡。为了维持活性氧平衡和细胞存活,脊椎动物通过线粒体自噬受体激活线粒体自噬以选择性地清除破损的线粒体。然而,在海洋无脊椎动物中,线粒体自噬及其功能在很大程度上是未知的。在该研究中,我们发现灿烂弧菌感染会破坏刺参(Apostichopus japonicus)体腔细胞线粒体的形态。此外,还检测到病原胁迫后体腔细胞线粒体膜电位降低以及线粒体自噬体的形成。线粒体和溶酶体的共定位进一步表明LPS胁迫增加了线粒体自噬通量。为了探究线粒体自噬的调控机制,我们在刺参中克隆获得了一种线粒体自噬的常见受体Bcl2/腺病毒E1B 19 kDa蛋白相互作用蛋白3(BNIP3),并证实AjBNIP3在灿烂弧菌感染和LPS胁迫后显著表达并积累在线粒体中。在线粒体膜上,AjBNIP3与自噬小体膜上的微管相关蛋白1轻链3(LC3)相互作用以介导线粒体自噬发生。干扰AjBNIP3后,线粒体自噬通量显著降低。此外,我们通过添加外源H2O2、ROS清除剂和ROS抑制剂证实了ROS可以激活AjBNIP3介导的线粒体自噬。最后,我们发现AjBNIP3 siRNA或高浓度乳酸均会抑制BNIP3介导的线粒体自噬,进而导致细胞凋亡增加和体腔细胞存活率降低。总之,这些发现强调了AjBNIP3在线粒体自噬降解受损线粒体的过程中具有重要作用。这种线粒体自噬活性对应对灿烂弧菌感染的刺参体腔细胞的存活是必需的。

     

    Abstract: Organisms produce high levels of reactive oxygen species (ROS) to kill pathogens or act as signaling molecules to induce immune responses; however, excessive ROS can result in cell death. To maintain ROS balance and cell survival, mitophagy selectively eliminates damaged mitochondria via mitophagy receptors in vertebrates. In marine invertebrates, however, mitophagy and its functions remain largely unknown. In the current study, Vibrio splendidus infection damaged mitochondrial morphology in coelomocytes and reduced mitochondrial membrane potential (ΔΨm) and mitophagosome formation. The colocalization of mitochondria and lysosomes further confirmed that lipopolysaccharide (LPS) treatment increased mitophagy flux. To explore the regulatory mechanism of mitophagy, we cloned Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a common mitophagy receptor, from sea cucumber Apostichopus japonicus (AjBNIP3) and confirmed that AjBNIP3 was significantly induced and accumulated in mitochondria after V. splendidus infection and LPS exposure. At the mitochondrial membrane, AjBNIP3 interacts with microtubule-associated protein 1 light chain 3 (LC3) on phagophore membranes to mediate mitophagy. After AjBNIP3 interference, mitophagy flux decreased significantly. Furthermore, AjBNIP3-mediated mitophagy was activated by ROS following the addition of exogenous hydrogen peroxide (H2O2), ROS scavengers, and ROS inhibitors. Finally, inhibition of BNIP3-mediated mitophagy by AjBNIP3 small interfering RNA (siRNA) or high concentrations of lactate increased apoptosis and decreased coelomocyte survival. These findings highlight the essential role of AjBNIP3 in damaged mitochondrial degradation during mitophagy. This mitophagy activity is required for coelomocyte survival in A. japonicus against V. splendidus infection.

     

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