ABCB10 Regulates Early Steps of Heme Synthesis
Rationale: Heme plays a critical role in gas exchange, mitochondrial energy production and antioxidant defenses in cardiovascular system. The mitochondrial transporter ATP-binding cassette (ABC) B10 has been suggested to export heme out of the mitochondria and is required for normal hemoglobinization of erythropoietic cells and protection against ischemia-reperfusion injury in the heart; however, its primary function has not been established.
Objective: The aim of this study was to identify the function of ABCB10 in heme synthesis in cardiac cells.
Methods and Results: Knockdown of ABCB10 in cardiac myoblasts significantly reduced heme levels and the activities of heme-containing proteins, while supplementation with δ-aminolevulinic acid (ALA) reversed these defects. Overexpression of mitochondrial ALA synthase 2 (ALAS2), the rate-limiting enzyme upstream of ALA export, failed to restore heme levels in cells with ABCB10 downregulation. ABCB10 and heme levels were increased by hypoxia, and reversal of ABCB10 upregulation caused oxidative stress and cell death. Moreover, ABCB10 knockdown in neonatal rat cardiomyocytes (NRCM) resulted in a significant delay of calcium removal from the cytoplasm, suggesting a relaxation defect. Finally, ABCB10 expression and heme levels were altered in failing human hearts and mice with ischemic cardiomyopathy.
Conclusions: ABCB10 plays a critical role in heme synthesis pathway by facilitating ALA production or export from the mitochondria. In contrast to previous reports, we show that ABCB10 is not a heme exporter, and instead is required for the early mitochondrial steps of heme biosynthesis.
- aminolevulinic acid
- ischemic cardiomyopathy
- ATP-bining cassette proteins
- ion channel
- molecular biology
- calcium transients
- Received April 9, 2013.
- Revision received May 28, 2013.
- Accepted May 29, 2013.