PMC:3023298 / 22557-24507 JSONTXT

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mitochondrial ANT family in human consists of 3 members (ANT1-3, or solute carrier family 25, members 4, 5, and 6) encoded by three different genes, but in mouse only two isoforms of the ANT are present [65]. The proteins are ~33 kDa and function as homodimers [65]. They are multi-pass membrane proteins, with odd-numbered transmembrane helices that mediate exchange of cytosolic ADP for mitochondrial ATP across the inner membrane utilizing the electrochemical gradient [66]. These helices have kinks because of proline residues [66]. ANT1 binds VDAC1, CyPD, Bax, twinkle (ataxin-8), and cyclophilin-40; ANT2 binds VDAC1-3 and cyclophilin-40; ANT3 binds VDAC1, steroid sulfatase, and translocase of inner mitochondrial membrane-13 (TIMM13) and TIMM23 [65]. The ANT isoforms are expressed differentially in tissue- and species-specific patterns [67]. ANT1 is expressed highly in human and mouse heart and skeletal muscle; human brain has low ANT1 mRNA but high ANT3 mRNA, while mouse brain has high ANT1 mRNA [67]. ANT2 mRNA is very low or not expressed in most adult human and mouse tissues, except kidney [67]. In tissue mitochondria where more than one ANT isoform is expressed, it is ANT1 that binds preferentially to CyPD to form the mPTP at contact sites between the IMM and OMM (Figure 1) [68]. It has been proposed that, in the presence of high mitochondrial Ca2+, the binding of CyPD to proline residue 61 (Pro61) in loop 1 of ANT1 results in a conformation that converts the ANT into a non-specific pore [65]. Non-conditional ANT1 null mice are viable and grow normally but develop mitochondrial skeletal myopathy and cardiomyopathy [66]. Ablation both ANT isoforms in mouse liver surprisingly did not change fundamentally mPT and cell death in hepatocytes [69], and some ANT ligands induce mitochondrial dysfunction and cytochrome c release independent of mPT [70]. Thus, the mechanisms of ANT-mediated cell deaths need further study."}