Direct thyroid hormone signalling via ADP-ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter.
Addition of triiodothyronine at 10 pM in vitro to hypothyroid rat liver mitochondria doubles the rate of the adenine nucleotide transporter at low ADP concentrations. Nicotinamide abolishes this effect in parallel with its inhibition of the ADP-ribosylation of an inner membrane protein identical in size to the transporter. Nicotinamide also renders euthyroid preparations indistinguishable from hypothyroid ones. A mechanism is offered to explain these findings in which it is proposed that the adenine nucleotide transporter is a true allosteric protein and that its covalent modification by ADP-ribosylation increases the stability of the less favoured externally-facing C-conformation and thus increases the proportion of transporters in this orientation: although the C-conformation is significantly more leaky to cations than the tight matrix-facing M-conformation, this enhances ADP import. This model is shown to offer an explanation not only for the transport effects of T3 but also for those of oxidative stress and ADP-ribosylation inhibitors on Ca2+, H+ and K+ transfer across the mitochondrial inner membrane. Ca2+ at 30 nM appears to stabilize the M-conformation of the transporter by a mechanism other than ADP-ribosylation.
Mowbray
J
J
Department of Biochemistry and Molecular Biology, University College London, UK.
Hardy
D L
DL
D000227:Adenine Nucleotides / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D007037:Hypothyroidism / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D010539:Permeability; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014284:Triiodothyronine / Q000494:pharmacology*
D000227:Adenine Nucleotides; D008565:Membrane Proteins; D014284:Triiodothyronine; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D009536:Niacinamide; D000226:Mitochondrial ADP, ATP Translocases; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium