Alterations in mitochondrial function and associated quality control programs, including mitochondrial-specific autophagy, termed mitophagy, are gaining increasing recognition in the context of disease. However, the role of mitophagy in organ transplant rejection remains poorly understood. Using mice deficient in Parkin, a ubiquitin ligase that tags damaged or dysfunctional mitochondria for autophagic clearance, we assessed the impact of Parkin-dependent mitophagy on skin-graft rejection. We observed accelerated graft loss in Parkin-deficient mice across multiple skin graft models. Immune cell distributions posttransplant were largely unperturbed compared to wild-type; however, the CD8+ T cells of Parkin-deficient mice expressed more T-bet, IFNγ, and Ki67, indicating greater priming toward effector function. This was accompanied by increased circulating levels of IL-12p70 in Parkin-deficient mice. Using a mixed leukocyte reaction, we demonstrated that naïve Parkin-deficient CD4+ and CD8+ T cells exhibit enhanced activation marker expression and proliferative responses to alloantigen, which were attenuated with administration of a pharmacological mitophagy inducer (p62-mediated mitophagy inducer), known to increase mitophagy in the absence of a functional PINK1-Parkin pathway. These findings indicate a role for Parkin-dependent mitophagy in curtailing skin-graft rejection.

中文翻译：

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线粒体自噬介质 Parkin 的缺陷加速了小鼠皮肤同种异体移植物的排斥反应


线粒体功能的改变和相关质量控制程序，包括线粒体特异性自噬，称为线粒体自噬，在疾病背景下越来越得到认可。然而，线粒体自噬在器官移植排斥反应中的作用仍然知之甚少。使用缺乏 Parkin（一种泛素连接酶，可标记受损或功能失调的线粒体以进行自噬清除）的小鼠，我们评估了 Parkin 依赖性线粒体自噬对皮肤移植排斥反应的影响。我们在多种皮肤移植模型中观察到 Parkin 缺陷小鼠的移植物损失加速。与野生型相比，移植后免疫细胞分布基本不受干扰;然而，Parkin 缺陷小鼠的 CD8 + T 细胞表达更多的 T-bet 、 IFNγ 和 Ki67，表明对效应器功能的启动能力更强。这伴随着 Parkin 缺陷小鼠中 IL-12p70 循环水平的增加。使用混合白细胞反应，我们证明幼稚的 Parkin 缺陷型 CD4 + 和 CD8 + T 细胞表现出增强的激活标志物表达和对同种异体抗原的增殖反应，这些反应在给药药理学线粒体自噬诱导剂 （p62 介导的线粒体自噬诱导剂） 后减弱，已知在没有功能性 PINK1-Parkin 通路的情况下增加线粒体自噬。这些发现表明 Parkin 依赖性线粒体自噬在减少皮肤移植排斥反应中的作用。