Regulation factors in the human energy supplying system.

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ATP synthase (FoF1) plays a central role in cellular energy metabolism, and is regulated to maintain ATP via membrane electrochemical potential and protein synthesis. To understand these, both the energetics and synthesis of FoF1 were studied. The gene structures of the alpha, beta and gamma subunits of human FoF1 were sequenced, because alpha3beta3gamma complex is the major component of F1 portion of FoF1. These genes were whown to have common features of house keeping genes which have no TATA box. There are only one each bona fide gene encoding for the alpha, beta and gamma subunits in a human genome. Comparison of the 5'-upstream regions of these genes indicated three common sequences (CS1, CS2 and CS3), suggesting that putative cis-elements coordinate the expressions of the three subunits genes. The multiple transcription initiation sites were found upstream of the initiation codon of the alpha and beta genes. The gene for the alpha subunit was 14 kbp in length and contained 12 exons interrupted by 11 introns. At least 13 Alu repeating sequences were found in the alpha gene. The isoforms of the gamma subunit were generated by alternate splicing, and the muscle specific transcript lacks exon 9 in a casette fashion (J.Biol.Chem. 268 : 24950 (1993) ; in bovine, FEBS Lett. 325 : 281 (1993)). A rapid muscle activity lowers cytoplasmic pH, which induced exclusion of exon 9, and this induction was inhibited by cycloheximide and protein kinase C inhibitors. In contrast, a high cytoplasmic pH resulte in the production of liver type gamma (J.Biol.Chem. 269 : in press, 1994). The dominating function of nuclear DNA over the mitochondrial DNA expression has been shown by the cytoplast experiments (J.Biol.Chem. 269 : in press, 1994). The factor regulating both replication and transcription of the mitochondrial DNA (called mtTF1) has been shown to have two isofoms (Biochem. Biophys. Res. Commun. 194 : 544 (1993)).