Structures and functions of mitochondrial ABC transporters

Abstract

A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters. Sequence analysis of mitochondrial ABC transportersMitochondria of most eukaryote species harbour 2-4 different ABC transporters that belong to the B subfamily of half transporters. The proteins contain an N-terminal transmembrane domain (TMD) and a C-terminal nucleotidebinding domain (NBD), which form homodimers for full functionality [1]. Plant and algal genomes additionally encode a unique ABC transporter, termed cytochrome c maturation (Ccm)AB, in which the TMD and NBD are encoded by separate genes. CcmAB is placed in the ABCI subfamily, see section 'CcmAB in plant mitochondria'. Phylogenetic relationship of mitochondrial transporters of the ABCB subfamilyAs a starting point for the discussion of recent crystal structures and functional data, we have reanalysed the phylogenetic relationships of B-type mitochondrial ABC transporters and their closest prokaryotic homologues (Figure 1). The CcmAB proteins were excluded from the phylogenetic analysis due to their large evolutionary distance from the other mitochondrial ABC transporters.Key words: ATP-binding cassette (ABC) transporter, glutathione, haem, iron, mitochondria, oxidative stress. Abbreviations: ABC, ATP-binding cassette; Aft, Activator of ferrous transport; ATM, ABC transporter of the mitochondria; Ccm, cytochrome c maturation; dALA, δ-amino levulinic acid; IRP1, iron regulatory protein 1; Mdl, multi-drug resistance-like; Mfrn, mitoferrin; NBD, nt-binding domain; PPIX, protoporphyrin IX; TMD, transmembrane domain; TMH, transmembrane helix. 1 To whom correspondence should be addressed (email janneke.balk@jic.ac.uk).The ABCB7 group, which includes the ABC transporters of the mitochondria Atm1 in yeast and ATM3 in Arabidopsis, can be found in virtually all eukaryotic species. Human ABCB7 and Arabidopsis ATM3 can largely rescue the phenotypes of yeast atm1 mutants [2][3][4], providing experimental support that members of this subfamily may have the same function. Human ABCB6 can also partially complement a yeast atm1 mutant [5] but differences in the intracellular localization of ABCB6 and Atm1 may point to distinct phys...

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