Aims/hypothesis Lon protease degrades oxidatively damaged proteins in mitochondrial matrix. To examine the relationships between mitochondrial quality control, mitochondrial functions and diabetes, we investigated whether lon protease deficiency influences insulin resistance by affecting mitochondrial function. Methods Lon protease-specific small interfering RNA (siRNA) was transfected into human liver SK-HEP-1 cells and changes in molecules related to insulin resistance were analysed. Results Reduction in lon protease was achieved using specific siRNA-induced mitochondrial dysfunction in human liver SK-HEP-1 cells. Concurrently, insulin signalling and subsequent insulin action were impaired and levels of gluconeogenic enzymes were increased by lon protein deficiency. Moreover, the activity of mitogen-activated protein kinases and transcription factors related to hepatic gluconeogenesis were elevated in LON (also known as LONP1) siRNA-transfected cells via increased intracellular reactive oxygen species production. Overproduction of lon protease restored mitochondrial function and also diminished the insulin resistance induced by treatment with cholesterol and palmitate. In addition, levels of lon protease decreased dramatically in livers of diabetic db/db mice compared with their lean mice counterparts. Conclusions/interpretationHere we have demonstrated that reduction of lon protease induced hepatic insulin resistance by lowering mitochondrial function. This is the first study to report that defects in mitochondrial protein quality control could cause insulin resistance and diabetes.

The complete 1141 bp mitochondrial cytochrome b sequences were determined for lenok Brachymystax lenok, cherry salmon Oncorhynchus masou masou, Ishikawa's cherry salmon O. m. ishikawai, chum salmon O. keta, rainbow trout O. mykiss, and an albino mutant of rainbow trout. Common substitutions detected in these species were transitional mutations. There were no significant differences in the intraspecific variation of the cytochrome b genes. Interspecific divergences were greater than intraspecific variation. The level of variation ranged from 8·026-15·686%. The cherry salmon was closer to chum salmon than to rainbow trout, and the lenok was the most distantly related species. 2000 The Fisheries Society of the British Isles