MDL1 and MDL2 encode members of the ATP-binding Cassette (ABC) transporter family that reside in the mitochondrial inner membrane (1, 2). They are classified as "half-molecule" family members because they are comprised of one transmembrane domain and one nucleotide-binding domain, in contrast to "full-size" family members in which this arrangement is repeated in tandem. Mdl1p and Mdl2p are similar to each other and to other ABC family members, in particular to human TAP1 and TAP2, which form a heterodimer that transports peptides from the cytoplasm into the endoplasmic reticulum (1). Defects in TAP1 and TAP2 are linked to bare lymphocyte syndrome (OMIM) and Wegener-like granulomatosis (OMIM).

Processing of Mdl1p during import into the mitochondrial inner membrane removes a 59-amino acid presequence (5). In the inner membrane, Mdl1p exists as a homodimer with the nucleotide-binding domains exposed to the mitochondrial matrix (2, 5). An mdl1 null mutation does not confer any obvious growth phenotypes and in particular does not affect respiratory growth; however, it does decrease the export of peptides 6-20 amino acids in length from mitochondria (2). Mutations in conserved regions of the ABC family (the Walker A or B motifs, or the C-loop motif) also block the export of such oligopeptides (2). These peptides are generated by the m-AAA protease (Afg3p and Yta12p) as it degrades unassembled or misfolded proteins in the mitochondrial matrix as part of the mitochondrial protein quality control system. The role of Mdl1p is thought to be the transport of these peptides across the inner membrane into the intermembrane space, from which they diffuse passively across the outer membrane through the TOM complex or via outer membrane channel proteins such as Por1p and Por2p (2). Purified Mdl1p reconstituted into liposomes does not transport random 8- or 23-amino acid peptides, suggesting that it may have a limited substrate specificity (6).

Null mutation or overexpression of MDL1 affects sensitivity to oxidative stress, and additionally the null mutant exhibits a genetic interaction with a null mutation in ATM1 encoding another mitochondrial ABC transporter that exports iron-sulfur clusters to the cytosol (3). These phenotypes could indicate a role for Mdl1p in oxidative stress resistance via export of peptides generated from the turnover of damaged proteins, or could indicate a functional interaction between Mdl1p and Atm1p (3).

Last updated: 2010-02-09