Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Institut Cochin, Unité U1016, INSERM, UMR 8104, CNRS, Université Paris 5, F-75014 Paris, France.
Cells. 2020 Sep 29;9(10):2197. doi: 10.3390/cells9102197.
Murine fibroblasts deficient in mitochondria respiratory complexes III (CIII) and IV (CIV) produced by either the ablation of (encoding for Rieske iron sulfur protein, RISP) or (encoding for protoheme IX farnesyltransferase, COX10) genes, respectively, showed a pleiotropic effect in complex I (CI). Exposure to 1-5% oxygen increased the levels of CI in both RISP and COX10 KO fibroblasts. De novo assembly of the respiratory complexes occurred at a faster rate and to higher levels in 1% oxygen compared to normoxia in both RISP and COX10 KO fibroblasts. Hypoxia did not affect the levels of assembly of CIII in the COX10 KO fibroblasts nor abrogated the genetic defect impairing CIV assembly. Mitochondrial signaling involving reactive oxygen species (ROS) has been implicated as necessary for HIF-1α stabilization in hypoxia. We did not observe increased ROS production in hypoxia. Exposure to low oxygen levels stabilized HIF-1α and increased CI levels in RISP and COX10 KO fibroblasts. Knockdown of HIF-1α during hypoxic conditions abrogated the beneficial effect of hypoxia on the stability/assembly of CI. These findings demonstrate that oxygen and HIF-1α regulate the assembly of respiratory complexes.
缺失线粒体呼吸复合物 III（CIII）和 IV（CIV）的鼠成纤维细胞，分别通过 （编码 Rieske 铁硫蛋白，RISP）或 （编码原卟啉 IX 法呢基转移酶，COX10）基因的消融产生，在复合物 I（CI）中表现出多效性。暴露于 1-5%氧气会增加 RISP 和 COX10 KO 成纤维细胞中 CI 的水平。在 1%氧气中，与常氧相比，新组装的呼吸复合物以更快的速度和更高的水平发生在 RISP 和 COX10 KO 成纤维细胞中。缺氧不会影响 COX10 KO 成纤维细胞中 CIII 的组装水平，也不会消除影响 CIV 组装的遗传缺陷。涉及活性氧（ROS）的线粒体信号已被认为是缺氧时 HIF-1α 稳定所必需的。我们没有观察到缺氧时 ROS 产生增加。暴露于低氧水平稳定了 HIF-1α 并增加了 RISP 和 COX10 KO 成纤维细胞中 CI 的水平。在缺氧条件下敲低 HIF-1α 会消除缺氧对 CI 稳定性/组装的有益影响。这些发现表明氧气和 HIF-1α 调节呼吸复合物的组装。
