Department of Medicine.
Department of Anesthesiology.
JCI Insight. 2017 Feb 9;2(3):e89676. doi: 10.1172/jci.insight.89676.
The heme oxygenase-1 (; HO-1) pathway was tested for defense of mitochondrial quality control in cardiomyocyte-specific KO mice (HO-1[CM]) exposed to oxidative stress (100% O). After 48 hours of exposure, these mice showed persistent cardiac inflammation and oxidative tissue damage that caused sarcomeric disruption, cardiomyocyte death, left ventricular dysfunction, and cardiomyopathy, while control hearts showed minimal damage. After hyperoxia, HO-1(CM) hearts showed suppression of the Pgc-1α/nuclear respiratory factor-1 (NRF-1) axis, swelling, low electron density mitochondria by electron microscopy (EM), increased cell death, and extensive collagen deposition. The damage mechanism involves structurally deficient autophagy/mitophagy, impaired LC3II processing, and failure to upregulate - and -mediated mitophagy. The mitophagy pathway was suppressed through loss of NRF-1 binding to proximal promoter sites on both genes. These results indicate that cardiac induction not only prevents heme toxicity, but also regulates the timing and registration of genetic programs for mitochondrial quality control that limit cell death, pathological remodeling, and cardiac fibrosis.
血红素加氧酶-1（HO-1）途径被测试用于防御心肌细胞特异性 KO 小鼠（HO-1[CM]）在氧化应激（100% O）下的线粒体质量控制。暴露 48 小时后，这些小鼠表现出持续的心脏炎症和氧化组织损伤，导致肌节破坏、心肌细胞死亡、左心室功能障碍和心肌病，而对照心脏显示出最小的损伤。在高氧后，HO-1(CM)心脏显示出 Pgc-1α/核呼吸因子-1（NRF-1）轴的抑制、肿胀、电子显微镜（EM）下低电子密度线粒体、细胞死亡增加和广泛的胶原沉积。损伤机制涉及结构缺陷的自噬/线粒体自噬、LC3II 处理受损以及不能上调 - 和 - 介导的线粒体自噬。线粒体自噬途径被抑制是由于 NRF-1 结合到这两个基因近端启动子位点的缺失。这些结果表明，心脏诱导不仅可以预防血红素毒性，还可以调节线粒体质量控制的遗传程序的时间和注册，从而限制细胞死亡、病理性重塑和心脏纤维化。
