PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses
PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses
复制标题
DOI：
10.1371/journal.pone.0218003
复制
发表时间：
2019-06-06
期刊：
影响因子：
3.7
通讯作者：
Mora, Ana L.
中科院分区：
文献类型：
--
作者：
Bueno, Marta;Zank, Daniel;Mora, Ana L.
我们先前已经证明内质网应激(内质网应激)抑制了肺泡II型上皮细胞(AECII)中PTEN诱导的激酶1(PINK1)，减少了有丝分裂，增加了肺纤维化的易感性。尽管慢性肺病患者循环中线粒体DNA(MtDNA)增多已有报道，但吞丝分裂在调节线粒体潮湿释放和激活促纤维化反应中的作用尚不清楚。在这项研究中，我们发现内质网应激和AECII中PINK1缺乏导致线粒体应激，线粒体DNA显著氧化和损伤，随后细胞外释放。在AECII中，TLR9通过内吞依赖途径识别细胞外mtDNA。依赖PINK1缺乏的线粒体DNA释放促进了TLR9的激活，并触发了促纤维化因子转化生长因子-β的分泌，而转化生长因子-β可被PINK1过表达所挽救。衰老和IPF患者肺组织线粒体DNA氧化和损伤增强，与之一致，IPF患者血浆和支气管肺泡灌洗液(BAL)中循环mtDNA水平显著升高。在其他PINK1低表达的ILD中，包括过敏性肺炎和自身免疫性间质性肺疾病，游离mtDNA水平均升高。这些结果支持了PINK1介导的丝裂原吞噬在抑制线粒体损伤相关分子模式(DAMP)的释放和控制转化生长因子-β介导的促纤维化反应中的作用。
We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-beta which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-beta mediated profibrotic responses.