ATP-dependent Mitochondrial Porphyrin Importer ABCB6 Protects against Phenylhydrazine Toxicity

Abstract

Background:The role of the mitochondrial ABC transporter, Abcb6, in vivo is unknown. Results: Abcb6-null mice are incapable of ATP-dependent import of mitochondrial porphyrins. Despite compensatory changes in the porphyrin pathway, Abcb6-null mice are less viable after a porphyrin-inducing stress. Conclusion: Abcb6 absence abolished ATP-dependent mitochondrial porphyrin uptake and deregulated porphyrin pathway genes. Significance: Disrupted Abcb6 function may produce porphyria after certain stresses.

Functional Coupling of ATP-binding Cassette Transporter Abcb6 to Cytochrome P450 Expression and Activity in Liver

“…This suggests that in vivo Abcb6 might not be important for basal porphyrin synthesis. These findings are consistent with recent reports that demonstrate a lack of functional association between Abcb6 and basal porphyrin synthesis in erythroid cells in vivo (18).…”

“…This observation is relatively consistent with recent reports of growth and proliferation defects associated with loss of Abcb6 function in humans and in zebrafish (22). Although Abcb6 is capable of transporting heme precursors into the mitochondria (17,18) and plays a role in regulating porphyrin synthesis in vitro (17,26), Abcb6 deficiency in vivo did not have a significant impact on hepatic porphyrin or heme levels. This suggests that in vivo Abcb6 might not be important for basal porphyrin synthesis.…”

“…1f). These results suggest that although Abcb6 is capable of transporting heme precursors into the mitochondria (18,27) and plays a role in regulating porphyrin synthesis in vitro (17,18,26), Abcb6 deficiency in vivo does not have a significant impact on basal hepatic porphyrin or heme levels. These findings are consistent with recent reports that demonstrate a lack of functional association between Abcb6 and basal porphyrin synthesis in erythroid cells in vivo (18).…”

“…ABCB6 was initially characterized as a mitochondrial transporter capable of regulating porphyrin synthesis (17). However, recent studies suggest that loss of Abcb6 expression in mice does not affect basal porphyrin synthesis (18). Consistent with this observation, in humans, loss of function mutations in the ABCB6 gene results in a variety of complex human diseases whose pathogenesis is independent of porphyrin synthesis (19 -23).…”

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

“…ABCB6 deficiency upregulates heme and iron pathways that are necessary for normal development. However, in conditions of extreme demand for porphyrins (such as during phenylhydrazine stress), these adaptations appear inadequate, suggesting the importance of ABCB6 for optimal survival under these stress conditions [40].…”