Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion.

BACKGROUND: Oxidative stress and mitochondrial dysfunction are central mediators of cardiac dysfunction after ischemia/reperfusion. ATP binding cassette mitochondrial erythroid (ABC-me; ABCB10; mABC2) is a mitochondrial transporter highly induced during erythroid differentiation and predominantly expressed in bone marrow, liver, and heart. Until now, ABC-me function in heart was unknown. Several lines of evidence demonstrate that the yeast ortholog of ABC-me protects against increased oxidative stress. Therefore, ABC-me is a potential modulator of the outcome of ischemia/reperfusion in the heart. METHODS AND RESULTS: Mice harboring 1 functional allele of ABC-me (ABC-me(+/-)) were generated by replacing ABC-me exons 2 and 3 with a neomycin resistance cassette. Cardiac function was assessed with Langendorff perfusion and echocardiography. Under basal conditions, ABC-me(+/-) mice had normal heart structure, hemodynamic function, mitochondrial respiration, and oxidative status. However, after ischemia/reperfusion, the recovery of hemodynamic function was reduced by 50% in ABC-me(+/-) hearts as a result of impairments in both systolic and diastolic function. This reduction was associated with impaired mitochondrial bioenergetic function and with oxidative damage to both mitochondrial lipids and sarcoplasmic reticulum calcium ATPase after reperfusion. Treatment of ABC-me(+/-) hearts with the superoxide dismutase/catalase mimetic EUK-207 prevented oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and restored mitochondrial and cardiac function to wild-type levels after reperfusion. CONCLUSIONS: Inactivation of 1 allele of ABC-me increases the susceptibility to oxidative stress induced by ischemia/reperfusion, leading to increased oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and to impaired functional recovery. Thus, ABC-me is a novel gene that determines the ability to tolerate cardiac ischemia/reperfusion.

Organellar vs cellular control of mitochondrial dynamics.

Mitochondrial dynamics, the fusion and fission of individual mitochondrial units, is critical to the exchange of the metabolic, genetic and proteomic contents of individual mitochondria. In this regard, fusion and fission events have been shown to modulate mitochondrial bioenergetics, as well as several cellular processes including fuel sensing, ATP production, autophagy, apoptosis, and the cell cycle. Regulation of the dynamic events of fusion and fission occur at two redundant and interactive levels. Locally, the microenvironment of the individual mitochondrion can alter its ability to fuse, divide or move through the cell. Globally, nuclear-encoded processes and cellular ionic and second messenger systems can alter or activate mitochondrial proteins, regulate mitochondrial dynamics and concomitantly change the condition of the mitochondrial population. In this review we investigate the different global and local signals that control mitochondrial biology. This discussion is carried out to clarify the different signals that impact the status of the mitochondrial population.

Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria.

Mitoferrin-1 (Mfrn1; Slc25a37), a member of the solute carrier family localized in the mitochondrial inner membrane, functions as an essential iron importer for the synthesis of mitochondrial heme and iron-sulfur clusters in erythroblasts. The biochemistry of Mfrn1-mediated iron transport into the mitochondria, however, is poorly understood. Here, we used the strategy of in vivo epitope-tagging affinity purification and mass spectrometry to investigate Mfrn1-mediated mitochondrial iron homeostasis. Abcb10, a mitochondrial inner membrane ATP-binding cassette transporter highly induced during erythroid maturation in hematopoietic tissues, was found as one key protein that physically interacts with Mfrn1 during mouse erythroleukemia (MEL) cell differentiation. Mfrn1 was shown previously to have a longer protein half-life in differentiated MEL cells compared with undifferentiated cells. In this study, Abcb10 was found to enhance the stabilization of Mfrn1 protein in MEL cells and transfected heterologous COS7 cells. In undifferentiated MEL cells, cotransfected Abcb10 specifically interacts with Mfrn1 to enhance its protein stability and promote Mfrn1-dependent mitochondrial iron importation. The structural stabilization of the Mfrn1-Abcb10 complex demonstrates a previously uncharacterized function for Abcb10 in mitochondria. Furthermore, the binding domain of Mfrn1-Abcb10 interaction maps to the N terminus of Mfrn1. These results suggest the tight regulation of mitochondrial iron acquisition and heme synthesis in erythroblasts is mediated by both transcriptional and posttranslational mechanisms, whereby the high level of Mfrn1 is stabilized by oligomeric protein complexes.