Inhibition of mitochondrial oxidative phosphorylation induces hyper-expression of glutamic acid decarboxylase in pancreatic islet cells.
It has been hypothesised that mitochondrial dysfunction in pancreatic beta cells could produce hyper-expression of glutamic acid decarboxylase (GAD), a major autoantigen in insulin-dependent diabetes mellitus (IDDM) (Degli Esposti, M. and Mackay, I.R. Diabetologia 40: 352-356, 1997). Here we report that specific inhibition of mitochondrial respiration enhances the expression of GAD in both foetal mouse pancreatic tissue and hamster HIT-T15 cells. Inhibitors of NADH-ubiquinone oxidoreductase (complex I) seem to be particularly effective in increasing the expression of GAD in both foetal mouse pancreas and HIT-T15 hamster beta cells, especially in the presence of nutrients such as arginine and glucose. These results represent the first evidence that GAD expression is enhanced under conditions that are toxic to pancreatic beta cells, and establish a link between mitochondrial dysfunction and expression of IDDM autoantigens.
Myers
M A
MA
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Georgiou
H M
HM
Byron
S
S
Esposti
M D
MD
D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives; D001120:Arginine / Q000494:pharmacology; D002261:Carboxin / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D003603:Cytotoxins / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D006220:Haloperidol / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011863:Radioimmunoassay; D012378:Rodenticides / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D003603:Cytotoxins; D018492:Dopamine Antagonists; D005663:Furans; D007328:Insulin; D010671:Phenylurea Compounds; D012378:Rodenticides; D014475:Uncoupling Agents; D012402:Rotenone; C061022:bullatacin; C032456:antimycin; D002261:Carboxin; D000968:Antimycin A; D001120:Arginine; D005968:Glutamate Decarboxylase; D006220:Haloperidol; C012598:pyriminil