We assessed whether melatonin administration would prevent the hyperoxidative status that occurs in lung mitochondria with age. Mitochondria from lungs of male and female senescent prone mice at 5 and 10 months of age were studied. Age-dependent mitochondrial oxidative stress was evaluated by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and reductase activities. Mitochondrial respiratory chain and oxidative phosphorylation capability were also measured. Age induces a significant oxidative/nitrosative status in lung mitochondria, which exhibited a significantly reduced activity of the respiratory chain and ATP production. These manifestations of age were more pronounced in males than in females. After 9 months of melatonin administration in the drinking water, the hyperoxidative status and functional deficiency of aged lung mitochondria were totally counteracted, and had increased ATP production. The beneficial effects of melatonin were generally similar in both mice genders. Thus, melatonin administration, as a single therapy, maintained fully functioning lung mitochondria during aging, a finding with important consequences in the pathophysiology of lung aging. In view of these data melatonin, the production of which decreases with age, should be considered a preventive therapy against the hyperoxidative status of the aged lungs, and its use may lead to the avoidance of respiratory complications in the elderly.
KeywordsLung Aging Mitochondria Respiratory chain Oxidative phosphorylation Oxidative stress
The authors thank A. Puertas for technical assistance. This study was partially supported by grants from the Instituto de Salud Carlos III (RD06/0013/0008, PI08-1664), and from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P07-CTS-03135 and CTS-101).
- Brusque AM, Rosa RB, Schuck PF, Dalcin KB, Ribeiro CAJ, Silva CG, Wannmacher CMD, Dutra-Filho CS, Wyse ATS, Briones P, Wajner M (2002) Inhibition of the mitochondrial respiratory chain complex activities in rat cerebral cortex by methylmalonic acid. Neurochem Int 40:593–601PubMedCrossRefGoogle Scholar
- Caballero B, Vega-Naredo I, Sierra V, Huidobro-Fernández C, Soria-Valles C, De Gonzalo-Calvo D, Tolivia D, Pallás M, Camins A, Rodríguez-Colunga MJ, Coto-Montes A (2009) Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. J Pineal Res 46:106–114PubMedCrossRefGoogle Scholar
- Crespo E, Macías M, Pozo D, Escames G, Martín M, Vives F, Guerrero JM, Acuña-Castroviejo D (1999) Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J 13:1537–1546PubMedGoogle Scholar
- Jou MJ, Peng TI, Hsu LF, Jou SB, Reiter RJ, Yang CM, Chiao CC, Lin YF, Chen CC (2010) Visualization of melatonin's multiple mitochondrial levels of protection against mitochondrial Ca(2+)-mediated permeability transition and beyond in rat brain astrocytes. J Pineal Res 48:20–38PubMedCrossRefGoogle Scholar
- López LC, Escames G, Tapias V, Utrilla MP, León J, Acuña-Castroviejo D (2006) Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice. Its relation with mitochondrial dysfunction and prevention by melatonin. Int J Biochem Cell Biol 38:267–278PubMedCrossRefGoogle Scholar
- Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:57–60Google Scholar