Melatonin restores the mitochondrial production of ATP in septic mice.

OBJECTIVES: To evaluate the changes in the mitochondrial ATP production during sepsis and the participation of iNOS in these changes. We also assessed the effect of melatonin administration in this experimental paradigm.

METHODS: The activity of ATPase, the level of adenine nucleotides, and the ATP production were measured in mitochondria of diaphragm and hind leg skeletal muscle of wild type (iNOS+/+) and knockout iNOS (iNOS-/-) mice. Three experimental groups were done: control group; group of septic mice induced by cecal ligation and puncture (CLP), and group of septic mice treated with melatonin. Mice were killed 24 hours after CLP. Melatonin was administrated in four doses (30 mg/kg b.w.) as follows: 30 min before CLP (i.p.) and 30 min, 4 h and 8 h after CLP (s.c.).

RESULTS: Mitochondrial production of ATP decreased in iNOS+/+ but not in iNOS-/- mice after sepsis. No changes in the ATPase activity were found in any group. Melatonin treatment normalized the production of ATP in iNOS+/+ mice, without affecting iNOS-/- animals.

CONCLUSIONS: The reduction of the ATP production in iNOS+/+ but not in iNOS-/- mice suggest the participation of iNOS in the impairment of mitochondrial function in the former. Because ATPase was unaffected by sepsis, it is suggested the ATP deficit depended on the sepsis-induced respiratory chain damage. The normalization of the production of ATP with melatonin may explain the reduction of the mortality reported elsewhere in experimental and clinical sepsis after treatment with the indoleamine.