Biology of Mitochondrial ABCs and Their Contribution to Pathology

The mitochondria are key determinants in the life and death of a cell, and abnormalities in mitochondrial function are associated with a number of pathological conditions. Given that many crucial co-factors are generated in mitochondria, including heme and iron–sulfur clusters, it is a reasonable expectation that energy-dependent transporters might facilitate the efficient movement of these molecules through membrane barriers to their next enzymatic steps. The four mitochondrial ABC transporters are ABCB6, ABCB7, ABCB8, and ABCB10. Of these, ABCB6, ABCB7, and ABCB10 have been implicated in processes important to erythroid cells. Mitochondria are also the site of energy production, during which cytotoxic reactive oxygen species are generated. Through modulation of iron and heme biosynthesis, all four mitochondrial ABC transporters have important roles in protecting cells against excessive ROS. In humans, loss-of-function mutations in ABCB7 cause X-linked sideroblastic anemia with ataxia, and several variants that result in loss of ABCB6 at the surface of red cells have been used to identify a new blood group, Lan. ABCB8 has an important role in ischemia. Two of the mammalian mitochondrial transporters, ABCB6 and ABCB7, are closely related to homologs which serve to protect lower organisms from heavy metal toxicity, and mammalian ABCB6 has been demonstrated to provide resistance against some toxic metals, though the mechanism remains unclear. The physiology of mitochondrial transporters and how they contribute to pathological states will be discussed.