PDF(Pubmed)
Abstract：
A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.
摘要：
稳定的线粒体池对健康的细胞功能和生存至关重要。改变氧化还原生物学可以通过诱导多种细胞死亡和存活途径对线粒体产生不利影响。然而，对线粒体及其在原代人类细胞和特定疾病状态中的功能障碍的理解，包括哮喘,是谦虚的。铁凋亡传统上被认为是铁依赖的，氢过氧磷脂执行过程，诱导细胞溶质和线粒体损伤以驱动程序性细胞死亡。然而,在这份报告中，我们确定了一种脂氧合酶，在功能失调的线粒体亚群中发生的区室靶向铁凋亡相关的过氧化过程，不会促进细胞死亡。相反，这种线粒体过氧化过程与PTEN诱导的激酶（PINK）-1（PINK1）-Parkin-Optineurin介导的线粒体自噬紧密结合，以保护功能性线粒体库并防止细胞死亡。这些结合的过氧化过程导致上皮细胞表型的改变和纤毛细胞的损失，这与哮喘严重程度的恶化有关。Ferroptosis靶向干预这一过程可以保护健康的线粒体，逆转细胞表型变化并改善疾病预后。
