Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with the rodenticide Vacor
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M D Esposti1, A Ngo, M A Myers
1Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Abstract:
Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N'-p-nitrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDM. We report here that Vacor specifically inhibits the NADH:ubiquinone reductase activity of complex I in mammalian mitochondria. The activity of other respiratory enzymes of mitochondria is unaffected by Vacor at concentrations that completely inhibit the redox and energetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in insulinoma cells and pancreatic islets and is also consistent with the doses reported in cases of human poisoning. These results indicate that the toxic and diabetogenic action of Vacor primarily derives from the inhibition of mitochondrial respiration of NAD-linked substrates in the high-energy demanding cells of the pancreatic islets. This newly identified mechanism of the pathological effects resulting from Vacor intoxication could constitute a paradigm in which to understand environmental or metabolic causes of IDDM.
Insights
The rodenticide Vacor causes type 1 diabetes by inhibiting mitochondrial complex I. This disrupts energy production in pancreatic cells, leading to reduced insulin release and acute diabetes.
Area of Science:
- Biochemistry
- Toxicology
- Endocrinology
Background:
- Human intoxication with the rodenticide Vacor is known to induce acute insulin-dependent diabetes mellitus (IDDM).
- The precise molecular mechanism underlying Vacor's diabetogenic effects has remained largely unelucidated.
Purpose of the Study:
- To investigate the specific molecular target and mechanism through which Vacor exerts its toxic and diabetogenic effects.
- To determine if Vacor's action on mitochondrial respiration is linked to impaired insulin secretion.
Main Methods:
- Assessed the effect of Vacor on the activity of mitochondrial respiratory chain complexes, specifically complex I (NADH:ubiquinone reductase).
- Measured insulin release from insulinoma cells and pancreatic islets in the presence of Vacor.
- Correlated Vacor's inhibitory effects on complex I activity with its impact on insulin secretion.
Main Results:
- Vacor specifically inhibits the NADH:ubiquinone reductase activity of mitochondrial complex I in mammalian systems.
- Other mitochondrial respiratory enzyme activities were unaffected at concentrations that abolished complex I function.
- Vacor's inhibition of complex I activity directly correlated with the inhibition of insulin release from pancreatic cells.
Conclusions:
- Vacor's toxic and diabetogenic action stems primarily from the specific inhibition of mitochondrial complex I.
- This disruption of mitochondrial respiration in pancreatic islet cells impairs insulin release, causing acute IDDM.
- The findings propose a novel mechanism for IDDM pathogenesis, potentially applicable to environmental or metabolic causes.