Post-translational regulation of PGC-1α modulates fibrotic repair.
Post-translational regulation of PGC-1α modulates fibrotic repair.
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PGC-1α的翻译后调节调节纤维化修复
DOI：
10.1096/fj.202100339r
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Carter AB
中科院分区：
文献类型：
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作者：
Larson-Casey JL;Gu L;Davis D;Cai GQ;Ding Q;He C;Carter AB
特发性肺纤维化（IPF）是一种与线粒体氧化应激相关的进行性肺部疾病。线粒体活性氧 (mtROS) 通过调节线粒体动力学对细胞稳态非常重要。在这里，我们发现 IPF BAL 细胞表现出线粒体生物发生增加，部分原因是过氧化物酶体增殖物激活受体 -ɣ (PPARɣ) 共激活剂 (PGC)-1α 的核表达增加。 PPARGC1A mRNA 表达增加与 IPF 受试者肺功能下降直接相关。氧化剂介导的 p38 MAPK 通过 Akt1 调节 PGC-1α 激活，从而增加单核细胞来源的巨噬细胞中的线粒体生物合成。在单核细胞源性巨噬细胞中条件性删除 Ppargc1a 的小鼠或给予线粒体分裂化学抑制剂的小鼠的生物发生减少和细胞凋亡增加，并且小鼠免受肺纤维化的影响，证明了 PGC-1α 在纤维化修复中的重要性。这些观察结果表明，Akt1 介导的 PGC-1α 调节可维持单核细胞来源的巨噬细胞中的线粒体稳态，从而诱导细胞凋亡抵抗，从而导致肺纤维化的发病机制。
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator‐activated receptor‐ɣ (PPARɣ) coactivator (PGC)‐1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant‐mediated activation of the p38 MAPK via Akt1 regulated PGC‐1α activation to increase mitochondrial biogenesis in monocyte‐derived macrophages. Demonstrating the importance of PGC‐1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte‐derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1‐mediated regulation of PGC‐1α maintains mitochondrial homeostasis in monocyte‐derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.