Mechanisms of organ resistance and susceptibility to ferroptosis in a disease model of iron overload

铁死亡被定义为一种铁依赖性的细胞死亡形式，导致基于脂质的活性氧（ROS）的致命积累。铁在铁凋亡过程中发挥多重作用，包括氧化还原依赖性和氧化还原非依赖性作用。到目前为止，人们对整个机体水平上铁调节机制的损害是如何导致铁下垂的知之甚少。在我们之前的工作中，我们已经建立了一个小鼠模型，其hepcidin/铁转运蛋白调节轴[Fpn（C326S）小鼠]被破坏，维持全身铁稳态。这些小鼠很好地反映了人类遗传性血色素沉着症4型的病理生理，并表现出高水平的铁过载，包括血浆铁和铁蛋白水平升高，高转铁蛋白饱和度和组织铁过载。与其他铁超载小鼠模型不同，纯合子Fpn（C326S）小鼠在7至14个月大时死亡，并伴有胰腺铁凋亡。在Fpn（C326S）小鼠中一个有趣的观察是，一些组织（如胰腺）受到铁超载的严重损害，而另一些组织（如肝脏）受到的影响较小，尽管这两个组织积累了相似的高水平的铁，导致类似水平的脂质过氧化。本提案的总体目的是了解铁如何影响铁超载疾病小鼠模型中的铁下垂和生存能力。我们的目标是确定保护（如肝脏）或敏感（如胰腺）器官对铁诱导损伤的机制。我们将进一步比较铁诱导的铁下垂与“经典”铁下垂模型的分子特征。我们期望获得的数据将有助于确定铁超载诱导的铁下垂敏感性的生物标志物。这些结果将有助于确定目前正在开发的抗铁下垂疗法可能适用于预防铁超载疾病的组织损伤。

Ferroptosis is defined as an iron-dependent form of regulated cell death leading to the lethal accumulation of lipid-based reactive oxygen species (ROS). Iron exerts multiple effects in the ferroptosis process, which include redox-dependent and redox-independent functions. So far, little is known how impairment of iron-regulatory mechanisms at the level of an entire organism contribute to ferroptosis. In our previous work, we have generated a mouse model with a disruption of the hepcidin/ferroportin regulatory axis [Fpn(C326S) mice] that maintains systemic iron homeostasis. These mice reflect well upon the pathophysiology of human hereditary hemochromatosis type 4 and show high levels of iron overload, including elevated plasma iron and ferritin levels, high transferrin saturation and tissue iron overload. Unlike other mouse models of iron overload, homozygous Fpn(C326S) mice die between 7 and 14 months of age involving ferroptosis of the pancreas. An interesting observation in Fpn(C326S) mice is that some tissues (e.g. the pancreas) are severely damaged by iron overload, while others (e.g. the liver) are less affected, although both tissues accumulate similarly high levels of iron causing similar levels of lipid peroxidation. The overall aim of this proposal is to understand how iron impacts on ferroptosis and viability in a mouse model of iron overload disease. We aim to identify mechanisms that protect (e.g. the liver) or sensitize (e.g. the pancreas) organs for iron-induced damage. We will further compare molecular signatures of iron-induced ferroptosis with “classic” ferroptosis models. We expect that the data obtained will contribute to identify biomarkers for ferroptosis sensitivity induced by iron overload. These results will help to determine which of the anti-ferroptosis therapies currently in development may be applicable to prevent tissue damage in iron overload disorders.