We have previously shown that veratrine, a mixture of alkaloids known as Veratrum alkaloids, produces skeletal muscle toxicity, and there is evidence that veratrine interferes with the energetics of various systems, including cardiomyocytes and synaptosomes. In this work, we explored the effects of veratrine and veratridine, a component of this mixture, in rat skeletal muscle mitochondria and compared the results with those seen in liver mitochondria. Veratrine and veratridine alkaloids caused a significant concentration-dependent decrease in the rate of state 3 respiration, respiratory control (RCR) and ADP/O ratios in isolated rat skeletal muscle mitochondria (RMM), but not in rat liver mitochondria (RLM) supported by either NADH-linked substrates or succinate. The oxygen consumption experiments showed that RMM were more susceptible to the toxic action of Veratrum alkaloids than RLM. The addition of veratrine (250 microg/ml) to RMM caused dissipation of the mitochondrial electrical membrane potential during succinate oxidation, but this effect was totally reversed by adding ATP. These results indicate that there are chemical- and tissue-specific toxic effects of veratrine and veratridine on mitochondrial respiratory chain complexes. Identification of the specific respiratory chain targets involved should provide a better understanding of the molecular mechanisms of the toxicity of these agents.