The metabolism of the African lungfish, 'Protopterus dolloi,' induced to aestivate in the laboratory, was examined. The potential importance of lipids, carbohydrates, amino acids "and ketone bodies as fuels during aestivation were examined by measuring the activities of key enzymes in these pathways. The results suggest lipids, carbohydrates and amino acids may be important fuel sources during aestivation, and that the down-regulation of enzymes is tissue-specific. The main metabolic change was a decline in the activity of cytochrome c oxidase (CCO) in liver and kidney during aestivation. This decline was likely accomplished by the combined effects of a reduction in the amount of CCO protein (based on expression of subunit I) and the reduction in the amount of cardiolipin (CL), in the mitochondrial membrane. Levels of mRNA expression of CCO subunits I, II, III and IV did not change in the liver, however, in kidney the expression of subunits I and II were depressed by ~10-fold during aestivating, suggesting transcriptional regulation is tissue-specific. This study demonstrates that 'P. dolloi' undergo tissue-specific metabolic depression, and provides evidence for the role of CL in regulating CCO activity during aestivation.