Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL 60611, USA.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4152-7. doi: 10.1073/pnas.1119338109. Epub 2012 Feb 28.
Mitochondrial iron levels are tightly regulated, as iron is essential for the synthesis of Fe/S clusters and heme in the mitochondria, but high levels can cause oxidative stress. The ATP-binding cassette (ABC) transporter ABCB8 is a mitochondrial inner membrane protein with an unknown function. Here, we show that ABCB8 is involved in mitochondrial iron export and is essential for baseline cardiac function. Induced genetic deletion of ABCB8 in mouse hearts resulted in mitochondrial iron accumulation and cardiomyopathy, as assessed by echocardiography and invasive hemodynamics. Mice with ABCB8 deletion in the heart also displayed mitochondrial damage, and higher levels of reactive oxygen species and cell death. Down-regulation of ABCB8 in vitro resulted in decreased iron export from isolated mitochondria, whereas its overexpression had the opposite effect. Furthermore, ABCB8 is needed for the maturation of the cytosolic Fe/S proteins, as its deletion in vitro and in vivo led to decreased activity of cytosolic, but not mitochondrial, iron-sulfur-containing enzymes. These results indicate that ABCB8 is essential for normal cardiac function, maintenance of mitochondrial iron homeostasis and maturation of cytosolic Fe/S proteins. In summary, this report provides characterization of a protein involved in mitochondrial iron export.
线粒体铁水平受到严格调节，因为铁是线粒体中 Fe/S 簇和血红素合成所必需的，但高水平的铁会导致氧化应激。ATP 结合盒（ABC）转运蛋白 ABCB8 是一种线粒体内膜蛋白，其功能未知。在这里，我们表明 ABCB8 参与线粒体铁输出，并且是基础心脏功能所必需的。在小鼠心脏中诱导基因敲除 ABCB8 导致线粒体铁积累和心肌病，通过超声心动图和侵入性血液动力学评估。在心脏中敲除 ABCB8 的小鼠还表现出线粒体损伤，以及更高水平的活性氧和细胞死亡。体外下调 ABCB8 导致从分离的线粒体中减少铁输出，而其过表达则产生相反的效果。此外，ABCB8 是细胞质 Fe/S 蛋白成熟所必需的，因为其体外和体内敲除导致细胞质而不是线粒体含铁硫酶的活性降低。这些结果表明，ABCB8 对于正常的心脏功能、维持线粒体铁稳态和细胞质 Fe/S 蛋白的成熟是必需的。总之，本报告提供了一种参与线粒体铁输出的蛋白质的特征描述。
