The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

Abstract

The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-meÀ/À mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-meÀ/À erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-meÀ/À erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-meÀ/À erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. Cell Death and Differentiation (2012) 19, 1117-1126 doi:10.1038/cdd.2011; published online 13 January 2012A central event during erythroid development is the induction of the components responsible for heme biosynthesis. Although heme is also produced in non-erythroid cells, its biosynthesis is specifically regulated during erythroid differentiation. 1-3 Thus, mutations in some specific genes involved in heme production have been shown to cause several human blood disorders, such as sideroblastic anemias. 4 This type of anemia is characterized by abnormal erythroid differentiation with a reduction in the total number of erythrocytes. 4 In addition, there are idiopathic anemias (either genetic or druginduced) in which the primary molecular defect is unknown. Recently, a novel bioinformatic approach identified new genes involved in heme biosynthesis that could be potential therapeutic targets for these disorders. 5 Furthermore, this large-scale computational screen identified again the ATP Binding Cassette mitochondrial erythroid transporter (ABCme/ABCB10) as an important protein for heme biosynthesis. 5 We previously identified ABC-me as a downstream target of an essential transcription factor for terminal erythroid differentiation, namely GATA-1. 6 ABC-me is a homodimeric transporter located in the inner mitochondrial membrane, which shows the highest expression levels in erythroid tissues. 6,7 Importantly, during early stages of mouse development (day 10 post coitus, pc), ABC-me expression is detected exclusively at the primitive sites of hematopoiesis, namely the yolk sac blood islands. 6 Furthermore, at day 9.5-10.5 pc,...

Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways

“…Recent evidence suggests that ABCB10, a regulator of heme synthesis, helps protect against oxidative stress in vivo by peptide export and/or other molecules specifically regulating antioxidant function and/or avoiding mitochondrial oxidative damage. 33,34 Therefore, PL may elevate oxidative stress in pancreatic cancer cells by downregulating ABCB10.…”

Structures and functions of mitochondrial ABC transporters

“…ABCB10 homozygous knockout mice die in utero at 12 days. These embryos are white and produce very little haem [52]. Mice with one ABCB10 gene removed survived to become adults and were apparently normal, but their hearts were more susceptible to damage by oxidative stress during ischaemia and reperfusion [25].…”

Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states

“…ABCB10 expression is induced during erythroid differentiation and overexpression increases hemoglobin synthesis (12). However, ABCB10 is also expressed in many nonerythroid tissues, suggesting additional roles not related to hemoglobin synthesis (13,14). Interestingly, recent reports identified ABCB10 as a key player in protection against oxidative stress and processes intimately related to mitochondrial reactive oxygen species generation, such as cardiac recovery after ischemia and reperfusion (15,16).…”

“…Interestingly, recent reports identified ABCB10 as a key player in protection against oxidative stress and processes intimately related to mitochondrial reactive oxygen species generation, such as cardiac recovery after ischemia and reperfusion (15,16). ABCB10 knockout mice die at 12.5-d gestation, and were anemic at day 10.5, during a period where primitive erythropoiesis would normally occur (14). A potential role for ABCB10 would be export of a heme biosynthesis intermediate, in which case ABCB10 −/− mice would not be able to synthesize hemoglobin.…”