Proc. Natl. Acad. Sci. USA 109, 4152–4157 (2012)

Credit: HOSSEIN ARDEHALI

ATP-binding cassette (ABC) proteins transport various substrates across cell membranes, but the physiological importance of mitochondrial ABC proteins is only beginning to emerge. For example, ABCB8 localizes to the inner mitochondrial membrane and is known to have protective effects against oxidant-induced cell death, but its function is not known. Ichikawa et al. use a tamoxifen-dependent Cre recombinase to conditionally delete the gene encoding ABCB8 from cardiac tissue in mice, resulting in a progressive decrease in cardiac function consistent with cardiomyopathy. Mitochondrial architecture in cardiac tissue was damaged in knockout mice, and the organelles accumulated electron-dense material reminiscent of iron overload. In cultured cells, siRNA–mediated knockdown of ABCB8 resulted in mitochondrial iron accumulation, and overexpression of ABCB8 decreased mitochondrial iron content. The authors developed an assay to assess export of radiolabeled metals from mitochondria of HEK293 cells, confirming ABCB8-dependent iron but not phosphorus export. The authors also found that the activity of cytosolic but not mitochondrial Fe-S cluster–containing enzymes was compromised in cardiac tissue of ABCB8 knockout mice. These data indicate that ABCB8 is important for normal cardiac function and iron homeostasis.