Abstract 20467: Mitochondrial ATP-Binding Cassette Protein-1 Plays a Role in Mitochondrial Iron Homeostasis and Cytosolic Iron-Sulfur Protein Maturation, and Protects Against Doxorubicin-Induced Cardiomyopathy
Background: Mitochondria are the site of iron-sulfur (Fe/S) cluster formation; however, export of Fe/S clusters to the cytoplasm is not well characterized in mammalian cells. A novel mitochondrial protein, mitochondrial ATP-binding cassette protein-1 (mABC1), protects neonatal rat cardiomyocytes (NRCM) against oxidant-induced cell death; however, the primary function of this protein is not well characterized. We hypothesized that mABC1 is involved in Fe/S cluster export out of mitochondria, and protects against doxorubicin-induced cardiomyopathy by reducing mitochondrial iron levels.
Methods and Results: Downregulation of mABC1 by RNA interference in NRCM increased mitochondrial non-heme iron levels, reduced the activity of xanthine oxidase (a cytosolic Fe/S protein), and increased mitochondrial ROS production, whereas adenoviral mABC1 overexpression decreased mitochondrial non-heme iron levels and ROS production. To confirm these results, we generated tamoxifen-inducible heart-specific mABC1 knockout mice. As early as 4 weeks after mABC1 deletion, mice displayed cardiac dysfunction which was associated with mitochondrial iron accumulation, higher levels of ROS production, and reduced activity of a cytosolic Fe/S protein. Furthermore, mABC1 knockout hearts exhibited disarranged and smaller mitochondria. We then studied whether mABC1 overexpression protects against doxorubicin-induced cardiomyopathy, a disorder thought to be due to iron accumulation and resultant oxidant stress in cardiomyocytes. In NRCM, doxorubicin caused an increase in mitochondrial iron levels and mABC1 overexpression reversed this effect. Transgenic mice overexpressing mABC1 in the heart were protected against doxorubicin-induced cardiomyopathy and displayed normal cardiac function. Additionally, the hearts of these mice showed reduced mitochondrial iron levels and preserved mitochondrial structure.
Conclusions: Collectively, our results indicate that mABC1 is essential for normal cellular function by regulating mitochondrial iron homeostasis, cellular ROS production, and maturation of cytosolic Fe/S proteins. Furthermore, overexpression of mABC1 is protective against doxorubicin-induced cardiomyopathy.
- © 2010 by American Heart Association, Inc.