Mitochondrial ADP/ATP and phosphate carriers (ATP synthasome substrate carriers); SLC25A4/A5/A6 + SLC25A3

Oxidative phosphorylation is completed not only by the five respiratory complexes but by the inner-membrane carriers that supply ATP synthase (Complex V) with its substrates and export its product. Because the inner membrane is impermeable to adenine nucleotides and phosphate, two SLC25 mitochondrial-carrier activities are essential: the ADP/ATP translocase (adenine nucleotide translocator, ANT) and the phosphate carrier (PiC). The ADP/ATP translocase is an electrogenic antiporter that imports cytosolic ADP into the matrix in exchange for newly synthesised ATP, exporting the ATP made by Complex V; humans express three near-identical isoforms with tissue-specific distribution — ANT1/SLC25A4 (heart and skeletal muscle), ANT2/SLC25A5 (proliferative and glycolytic tissues) and ANT3/SLC25A6 (ubiquitous). The phosphate carrier SLC25A3 (PiC) imports inorganic phosphate into the matrix in symport with a proton, providing the Pi consumed by ATP synthase. ANT, PiC and ATP synthase physically associate as the "ATP synthasome", coupling substrate delivery to ATP synthesis. The ADP/ATP translocase also forms part of the mitochondrial permeability transition pore and participates in apoptosis (curated as non-core roles). Disorders: ANT1 (SLC25A4) mutations cause autosomal-dominant progressive external ophthalmoplegia and mitochondrial myopathy/cardiomyopathy; SLC25A3 defects cause a mitochondrial phosphate-carrier deficiency with lactic acidosis and hypertrophic cardiomyopathy.