Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung.
Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung.
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DOI：
10.1186/s12931-021-01640-z
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发表时间：
2021-02-08
影响因子：
5.8
通讯作者：
Romero F
中科院分区：
文献类型：
--
作者：
Cuevas-Mora K;Roque W;Shaghaghi H;Gochuico BR;Rosas IO;Summer R;Romero F
线粒体功能障碍已成为特发性肺纤维化（IPF）发病机制的重要参与者，IPF是成人特发性间质性肺病的常见原因。Hermansky-Pudlak综合征（HPS）是一种罕见的常染色体隐性遗传病，在年轻人中引起类似类型的肺纤维化，尽管线粒体功能障碍在这种情况下的作用尚不清楚。我们进行了详细的表征线粒体结构和功能的肺组织和肺泡上皮细胞缺乏的衔接蛋白复合物3 β 1（Ap 3b 1）亚基，基因负责引起亚型2的HPS（HPS-2）。我们观察到HPS-2细胞线粒体稳态的广泛变化，包括获得形状异常的线粒体，嵴数量减少，电子传递链和三羧酸循环的活性显着降低。我们还发现，线粒体氧化还原失衡和活性的线粒体未折叠蛋白反应失调的HPS-2细胞，这与各种其他的变化，似乎是补偿线粒体功能障碍。这包括糖酵解活性的增加，线粒体生物合成因子表达的上调和能量保存酶AMP活化蛋白激酶的活化增强。总之，我们的研究结果表明，线粒体功能在HPS-2肺组织中发生了显着改变，这表明该细胞器的功能障碍可能是HPS肺病的驱动因素。
Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood. We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2). We observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase. In summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.
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影响因子：
3.7
作者：
Hengst, Meike;Naehrlich, Lutz;Griese, Matthias
通讯作者：
Griese, Matthias
影响因子：
16
作者：
Dell'Angelica, EC;Shotelersuk, V;Bonifacino, JS
通讯作者：
Bonifacino, JS
影响因子：
29
作者：
Scialò F;Sriram A;Fernández-Ayala D;Gubina N;Lõhmus M;Nelson G;Logan A;Cooper HM;Navas P;Enríquez JA;Murphy MP;Sanz A
通讯作者：
Sanz A
DOI：
10.1165/rcmb.2014-0343oc
发表时间：
2015-07-01
影响因子：
6.4
作者：
Romero, Freddy;Shah, Dilip;Summer, Ross
通讯作者：
Summer, Ross
影响因子：
8.3
作者：
Chambers, Rachel C;Mercer, Paul F
通讯作者：
Mercer, Paul F