Hippocampal mitochondrial dysfunction in rat aging

Abstract

Navarro A, Ló pez-Cepero JM, Bá ndez MJ, Sá nchez-Pino M-J, Gó mez C, Cadenas E, Boveris A. Hippocampal mitochondrial dysfunction in rat aging. Am J Physiol Regul Integr Comp Physiol 294: R501-R509, 2008. First published December 12, 2007 doi:10.1152/ajpregu.00492.2007.-Hippocampus mitochondrial dysfunction with impaired electron transfer and increased oxidative damage was observed upon rat aging. Hippocampal mitochondria of aged (12 mo) and senescent (20 mo) rats showed, compared with young (4 mo) rats, marked decreases in the rate of state 3 respiration with NAD-dependent substrates (32-51%) and in the activities of mitochondrial complexes I (57-73%) and IV (33-54%). The activity of mitochondrial nitric oxide synthase was also decreased, 53-66%, with age. These losses in enzymatic activity were more marked in the hippocampus than in brain cortex or in whole brain. The histochemical assay of mitochondrial complex IV in the hippocampus showed decreased staining upon aging. Oxidative damage, determined as the mitochondrial content of thiobarbituric-acid reactive substances (TBARS) and protein carbonyls, increased in aged and senescent hippocampus (66 -74% in TBARS and 48 -96% in carbonyls). A significant statistical correlation was observed between mitochondrial oxidative damage and enzymatic activity. Mitochondrial dysfunction with shortage of energy supply is considered a likely cause of dysfunction in aged hippocampus. mitochondrial nitric oxide synthase; reduced nicotinamide adenide dinucleotide dehydrogenase; cytochrome oxidase; oxidative damage MAMMALIAN AGING is characterized by a gradual and continuous loss, starting at full adulthood, of the quality of physiological functions and responses. The losses are more marked in the functions that depend on the integrated response of the central nervous system (19) than in the functions of the renal or cardiovascular systems. Mitochondria were brought to attention in mammalian aging biology because of the central role of mitochondria in producing biochemical energy (ATP) to meet cellular requirements in aerobic cells and to the decline of basal metabolic rate and of physical performance that are characteristic of aging (32).The free radical theory of aging, based on the pioneer works of Gerschman et al. (18) and Harman (20), considers that aging is caused by the continuous inactivation of biologically essential macromolecules and subcellular structures due to chemical modifications produced by reactions mediated by oxygen free radicals. When the free radical theory of aging is focused in mitochondria, it emerges as the mitochondrial theory of aging (6,21,32,47). Mitochondria are considered likely pacemakers of tissue aging because of their continuous production of superoxide radical (O 2•Ϫ ) and of nitric oxide (NO) and to the mitochondrial sensitivity to free radical-mediated oxidative damage (32).Aged mammalian brain shows a decreased capacity to produce ATP by oxidative phosphorylation, and it is considered that this decreased capacity for energy production ...

Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding

“…This brain area depends considerably on mitochondrial functionality as documented by the large number of papers describing agerelated mitochondrial dysfunctions such as decreased rate of electron transfer in complex I and complex IV, decreased membrane potential, and increased content of macromolecular oxidized products (Bagh et al 2011;Frenzel et al 2010;Gilmer et al 2010;Guevara et al 2009Guevara et al , 2011Navarro and Boveris 2010;Navarro et al 2008). In this brain area, we found that AL rats presented an age-related increase in TFAM amount, which was not associated with an increase in mtDNA content, but with a mtDNA decrease.…”

“…Here, we decided to measure not only TFAM amount and mtDNA content, but also the in vivo binding activity of TFAM in rat frontal cortex, one among the brain areas mostly affected by the age-related mitochondrial dysfunction (Navarro et al 2008;Navarro and Boveris 2010). In aged AL rats, we found age-related increased amount of TFAM, loss of mtDNA content, increased content of the 4.8-kb deletion, and decreased TFAM binding to mtDNA.…”

Comparação do treinamento físico de quatro e oito semanas sobre atividade da cadeia transportadora de elétrons e marcadores de estresse oxidativo em fígado de camundongos

“…Disfunções mitocondriais são caracterizadas pela redução do controle respiratório, diminuição no potencial de membrana e desacoplamento mitocondrial (15) . Essas alterações são observadas no envelhecimento e em situações patológicas (5,15) .…”

“…Essas alterações são observadas no envelhecimento e em situações patológicas (5,15) . Prejuízos na atividade do complexo IV, por exemplo, estão relacionados com a doença de Alzheimer (16) e do complexo I, com Parkinson (17) .…”

Age-Related Mitochondrial Changes after Traumatic Brain Injury

“…There is an ongoing debate concerning the magnitude of decline in mitochondrial respiration that occurs during normal aging (Gilmer et al, 2010). Some groups report extensive age-related declines in mitochondrial respiration (Chiu and Richardson, 1980;Cocco et al, 2005;Navarro et al, 2005Navarro et al, , 2008Petrosillo et al, 2008a,b). Our laboratory and others (Bustamante et al, 2008;Deshmukh et al, 1980;Gilmer et al, 2010;Leslie et al, 1985;Meng et al, 2007) previously reported no significant age-related changes in cortical mitochondrial bioenergetics in naïve rats, while significant elevations in oxidative damage were apparent (Gilmer et al, 2010).…”