Mitochondrial carrier family (SLC25) transporters regulate cell physiology by coordinating mitochondrial metabolites. In mammals, SLC25A3 has dual functions importing both copper and phosphate to the matrix. Although a single SLC25A3 transporter is present in mammals, at least two paralogs were present in the last eukaryotic common ancestor that correspond to two SLC25 proteins in yeast: PIC2, the major copper transporter and MIR1, the major phosphate carrier. Evolutionary analyses informed site-directed mutagenesis experiments to interrogate the copper-transporting function in the SCL25A3. 

The Cobine lab demonstrated that copper and phosphate transport can be separated and reveal residues responsible for substrate selectivity. In addition, they have found that SLC25A3 is required to maintain the stability and activity of several cytosolic copper dependent enzymes as well as new targets of copper in mitochondria. The potential mechanism of the connection between SLC25A3 and these targets has been interrogated by genetic and pharmacological interventions and the advances to understand the diverse phenotypes that they have uncovered will be discussed.