Mechanism of mitochondrial adenine nucleotide homeostasis.
Xiaowen Wang, Blanka Kucejova, Xin Jie Chen
Department of Molecular Biolog, University of Texas Southweste, 5323 Harry Hines Blv, Dallas, TX, 75390-9148, USA
Adenine nucleotide homeostasis is critically important not only for oxidative phosphorylation, but also for mitochondrial biogenesis. Adenine nucleotide translocase (Ant) is a well studied mitochondrial inner membrane transporter that catalyzes the ADP/ATP exchange between the cytosol and the mitochondrial matrix. However, this 1:1 exchange does not alter the size of adenine nucleotide pools inside mitochondria. How the organelle meets the demand for adenine nucleotides during mitochondrial proliferation and cell division has been a long-standing question. We have shown that, although the three Ant isoforms of Saccharomyces cerevisiae equally support respiration (the R function), Aac2p and Aac3p, but not Aac1p, have an additional physiological function essential for cell viability (the V function). The V function is suppressed by SAL1 (for Suppressor of aac2-lethality), which encodes an evolutionarily conserved calcium-binding protein. Recent studies by other groups have shown that three putative Sal1p homologues in humans are capable of mediating the ATP-Mg/Pi exchange in in vitro reconstituted membranes. These observations suggest that the Sal1-family proteins most likely represent the long-sought after transporters that allow the net accumulation of adenine nucleotides in mitochondria. The genetic interaction between SAL1 and AAC2 prompted us to propose that the two genes define two parallel pathways that control mitochondrial adenine nucleotide homeostasis in yeast.