Monick Martha M, Powers Linda S, Barrett Christopher W, Hinde Sara, Ashare Alix, Groskreutz Dayna J, Nyunoya Toru, Coleman Mitchell, Spitz Douglas R, Hunninghake Gary W
Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242, USA.
J Immunol. 2008 Jun 1;180(11):7485-96. doi: 10.4049/jimmunol.180.11.7485.
A unique feature of human alveolar macrophages is their prolonged survival in the face of a stressful environment. We have shown previously that the ERK MAPK is constitutively active in these cells and is important in prolonging cell survival. This study examines the role of the ERK pathway in maintaining mitochondrial energy production. The data demonstrate that ATP levels in alveolar macrophages depend on intact mitochondria and optimal functioning of the electron transport chain. Significant levels of MEK and ERK localize to the mitochondria and inhibition of ERK activity induces an early and profound depletion in cellular ATP coincident with a loss of mitochondrial transmembrane potential. The effect of ERK suppression on ATP levels was specific, since it did not occur with PI3K/Akt, p38, or JNK suppression. ERK inhibition led to cytosolic release of mitochondrial proteins and caspase activation. Both ERK inhibition and mitochondrial blockers induced loss of plasma membrane permeability and cell death. The cell death induced by ERK inhibition had hallmarks of both apoptotic (caspase activation) and necrotic (ATP loss) cell death. By blocking ERK inhibition-induced reactive oxygen species, caspase activation was prevented, although necrotic pathways continued to induce cell death. This suggests that mitochondrial dysfunction caused by ERK inhibition generates both apoptotic and necrotic cell death-inducing pathways. As a composite, these data demonstrate a novel mitochondrial role for ERK in maintaining mitochondrial membrane potential and ATP production in human alveolar macrophages.
人类肺泡巨噬细胞的一个独特特征是它们在应激环境中能长期存活。我们之前已经表明，ERK MAPK在这些细胞中持续激活，并且在延长细胞存活方面很重要。本研究探讨了ERK通路在维持线粒体能量产生中的作用。数据表明，肺泡巨噬细胞中的ATP水平取决于完整的线粒体和电子传递链的最佳功能。大量的MEK和ERK定位于线粒体，抑制ERK活性会导致细胞ATP早期且显著消耗，同时伴有线粒体跨膜电位的丧失。ERK抑制对ATP水平的影响是特异性的，因为在抑制PI3K/Akt、p38或JNK时并未出现这种情况。ERK抑制导致线粒体蛋白的胞质释放和半胱天冬酶激活。ERK抑制和线粒体阻滞剂均导致质膜通透性丧失和细胞死亡。ERK抑制诱导的细胞死亡具有凋亡（半胱天冬酶激活）和坏死（ATP丧失）细胞死亡的特征。通过阻断ERK抑制诱导的活性氧，可防止半胱天冬酶激活，尽管坏死途径继续诱导细胞死亡。这表明ERK抑制引起的线粒体功能障碍产生了凋亡和坏死细胞死亡诱导途径。综合来看，这些数据证明了ERK在维持人类肺泡巨噬细胞线粒体膜电位和ATP产生方面具有新的线粒体作用。
