Case Western Reserve University, School of Medicine, Department of Pharmacology, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Development. 2012 Aug;139(16):2966-77. doi: 10.1242/dev.079632. Epub 2012 Jul 4.
Carotenoids and their metabolites are widespread and exert key biological functions in living organisms. In vertebrates, the carotenoid oxygenase BCMO1 converts carotenoids such as β,β-carotene to retinoids, which are required for embryonic pattern formation and cell differentiation. Vertebrate genomes encode a structurally related protein named BCDO2 but its physiological function remains undefined. Here, we show that BCDO2 is expressed as an oxidative stress-regulated protein during zebrafish development. Targeted knockdown of this mitochondrial enzyme resulted in anemia at larval stages. Marker gene analysis and staining for hemoglobin revealed that erythropoiesis was not impaired but that erythrocytes underwent apoptosis in BCDO2-deficient larvae. To define the mechanism of this defect, we have analyzed the role of BCDO2 in human cell lines. We found that carotenoids caused oxidative stress in mitochondria that eventually led to cytochrome c release, proteolytic activation of caspase 3 and PARP1, and execution of the apoptotic pathway. Moreover, BCDO2 prevented this induction of the apoptotic pathway by carotenoids. Thus, our study identifying BCDO2 as a crucial protective component against oxidative stress establishes this enzyme as mitochondrial carotenoid scavenger and a gatekeeper of the intrinsic apoptotic pathway.
类胡萝卜素及其代谢物广泛存在，并在生物体中发挥关键的生物学功能。在脊椎动物中，类胡萝卜素加氧酶 BCMO1 将β，β-胡萝卜素等类胡萝卜素转化为视黄酸，这对视黄酸在胚胎形态形成和细胞分化中是必需的。脊椎动物基因组编码一种结构上相关的蛋白，命名为 BCDO2，但它的生理功能尚未确定。在这里，我们发现在斑马鱼发育过程中，BCDO2 作为一种氧化应激调节蛋白表达。该线粒体酶的靶向敲低导致幼虫期贫血。标记基因分析和血红蛋白染色表明，红细胞生成没有受损，但在 BCDO2 缺陷型幼虫中，红细胞发生凋亡。为了确定这种缺陷的机制，我们分析了 BCDO2 在人细胞系中的作用。我们发现类胡萝卜素在线粒体中引起氧化应激，最终导致细胞色素 c 释放、caspase 3 和 PARP1 的蛋白水解激活以及凋亡途径的执行。此外，BCDO2 可防止类胡萝卜素诱导的这种凋亡途径。因此，我们的研究将 BCDO2 鉴定为一种对抗氧化应激的关键保护成分，确立了该酶作为线粒体类胡萝卜素清除剂和内在凋亡途径的守门员。
