The mitochondrial electron transfer alteration as a factor involved in the brain aging

Benzi, G.; Pastoris, Ornella; Marzatico, Fulvio; Villa, R. F.; Dagani, F.; Curti, Daniela

doi:10.1016/0197-4580(92)90109-b

Cited by 128 publications

(64 citation statements)

References 51 publications

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“…5B) and decreased state 3 respiration in malate-pyruvate NAD-dependent substrate. These results are consistent with previous reports indicating a reduction in Complex I activity in mitochondria isolated from old brain, liver, kidney and skeletal muscle (Benzi et al, 1992;Kumaran et al, 2005;Lenaz et al, 1997;Nakahara et al, 1998;Navarro and Boveris, 2004;Sugiyama et al, 1993). These changes may contribute to the reduced energetic reserves and increased susceptibility of the aged heart to stress and oxidative injury (Navarro and Boveris, 2007), underscoring the relevance of the present findings.…”

Section: Discussionsupporting

confidence: 94%

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Preston¹,

Oberlin²,

Holmuhamedov³

et al. 2008

Mechanisms of Ageing and Development

126

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Aging is associated with progressive decline in energetic reserves compromising cardiac performance and tolerance to injury. Although deviations in mitochondrial functions have been documented in senescent heart, the molecular bases for the decline in energy metabolism are only partially understood. Here, high-throughput transcription profiles of genes coding for mitochondrial proteins in ventricles from adult (6-months) and aged (24-months) rats were compared using microarrays. Out of 614 genes encoding for mitochondrial proteins, 94 were differentially expressed with 95% downregulated in the aged. The majority of changes affected genes coding for proteins involved in oxidative phosphorylation (39), substrate metabolism (14) and tricarboxylic acid cycle (6). Compared to adult, gene expression changes in aged hearts translated into a reduced mitochondrial functional capacity, with decreased NADH-dehydrogenase and F0F1-ATPase complex activities and capacity for oxygen-utilization and ATP synthesis. Expression of genes coding for transcription co-activator factors involved in the regulation of mitochondrial metabolism and biogenesis were downregulated in aged ventricles without reduction in mitochondrial density. Thus, aging induces a selective decline in activities of oxidative phosphorylation complexes I and V within a broader transcriptional downregulation of mitochondrial genes, providing a substrate for reduced energetic efficiency associated with senescence.

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Section: Discussionsupporting

confidence: 94%

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Preston¹,

Oberlin²,

Holmuhamedov³

et al. 2008

Mechanisms of Ageing and Development

126

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“…In other studies, the rate of H 2 O 2 generation is observed to increase during aging even when SOD activity declines; however, the magnitude of the loss of SOD activity associated with aging is only a small fraction of the increase in SOD activity associated with development (23,55,56). This is also true of the change in COX, which decreases moderately in mammals during aging in vivo (28) but, as we demonstrate, increases dramatically during development.…”

Section: Discussionsupporting

confidence: 48%

“…Shifts in the redox environment resulting from the production of In contrast to previous reports of age-associated increases in generation of both ⅐ O 2 Ϫ and H 2 O 2 (9, 14), we observed no agingassociated increase in oxidation. In vivo, age-associated decreases in the activities of COX, ND, and to a lesser extent SD activities have been reported in a wide variety of mammalian species (28,63) including humans (64 -66). These changes are believed to play an important role in aging-dependent increases in oxidation in vivo (16,28).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, age-associated decreases in the activities of COX, ND, and to a lesser extent SD activities have been reported in a wide variety of mammalian species (28,63) including humans (64 -66). These changes are believed to play an important role in aging-dependent increases in oxidation in vivo (16,28). The aging-associated decreases in COX which occur in vivo appear to result from age-dependent changes in lipid-protein interactions (13,(67)(68)(69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

“…A second factor that can alter the rate of electron flow and the rate of cellular oxidant generation is the activity of the enzyme complexes that regulate electron entry and exit from the ETC. For example, an age-dependent decrease in cytochrome c oxidase (COX) activity has been implicated as one possible cause of the rise in ROS generation observed in aging insects (16) and in aging mammalian brains (28).…”

mentioning

confidence: 99%

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Development and Age-associated Differences in Electron Transport Potential and Consequences for Oxidant Generation

Allen

Keogh²,

Tresini

et al. 1997

Journal of Biological Chemistry

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We determined the activities of NADH dehydrogenase (ND), succinate dehydrogenase, and cytochrome c oxidase (COX) in 29 skin fibroblast lines established from donors ranging in age from 12 gestational weeks to 94 years. The results of this study demonstrate that all three of the enzyme activities examined are greater in adult-derived fibroblasts than in the fetal cell lines. The ratio of enzyme activities that control electron entry into and exit from the electron transport chain varied directly with lucigenin-detected chemiluminescence (an indicator of ⅐ O 2 ؊ generation) and inversely with H 2 O 2 generation. These results indicate a clear difference in the predominant oxidant species generated during fetal and adult stages of life. We also examined the mRNA abundances of different components of the electron transport chain complexes. We observed higher abundances of mitochondrial encoded mRNAs (COX 1 and ND 4) in cell lines established from adults than in fetal cells. No differences in the mRNA abundances of the nuclear encoded sequences (COX 4 and ND 51) were observed in fetal and postnatal-derived lines. Succinate dehydrogenase mRNA abundance was greater in cell lines established from postnatal donors than in fetal cell lines. No significant differences between cell lines established from young and old adults were detected in any of the parameters examined.Mitochondria are the primary site of aerobic energy production and are thus the major site of generation of reactive oxygen species (ROS), 1 such as oxygen-centered free radicals and peroxides, which are by-products of metabolism (1-4). Estimates of the rate of ROS generation can differ greatly; however, it has been demonstrated repeatedly that the relative rate of oxidant generation increases with age and that this increase correlates strongly with age-associated changes in the cellular redox state (5-8). For example, the rates of superoxide ( ⅐ O 2 Ϫ ) (8 -14) and H 2 O 2 generation (7, 10, 14 -17) increase in the cells of aging organisms, whereas the glutathione concentration declines progressively with advancing age (5,6,18,19). Differences in ROS metabolism also exist between cells obtained from early developmental stages and from postnatal tissues (for review, see Refs. 20 and 21). The activities of enzymic antioxidant defenses tend to be lower in fetal cells than in cells derived from postnatal tissues (22-24); however, the GSH concentration is frequently greater in fetal cells than in cells from adults (20,24). Whether these observations reflect differences in the steadystate level of ROS in fetal and postnatal cells is not presently known (20, 21).The rate of mitochondrial ROS generation in cells is largely dependent on the amounts of autoxidizable respiratory carriers and the redox state of electron carriers (1,3,25,26). All electron carriers located prior to one of low abundance will exhibit a greater propensity to be chemically reduced because of the slowing of electron flux (electron stacking; 1, 16, 25, 27). Thus, either age or development-a...

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Differences in electron transport potential, antioxidant defenses, and oxidant generation in young and senescent fetal lung fibroblasts (WI-38)

et al. 1999

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The activities and mRNA abundances of enzymes that regulate the rate of electron flow through the electron transport chain (ETC), including NADH dehydrogenase, succinate dehydrogenase, and cytochrome c oxidase, were examined in young and senescent fetal lung fibroblasts (WI-38). We also determined the activities and mRNA abundances of antioxidant defenses including superoxide dismutase, catalase, and glutathione peroxidase. We confirmed our previous report of a senescence-related increase in the abundance of ND4, a mitochondrially encoded subunit of NADH dehydrogenase. The activities of cytochrome c oxidase and NADH dehydrogenase were also elevated in senescent cultures. No differences were observed in the mRNA abundances of COX-1, a mitochondrially encoded subunit of cytochrome c oxidase or of nuclearly encoded subunits of various electron transport components (SD, COX-4, and ND 51). Lucigenin-detected chemiluminescence and H2O2 generation were both elevated in senescent cells. Catalase activity was also elevated in senescent fibroblasts. However, no differences in catalase mRNA abundance were observed. A small decrease in GSH peroxidase (GPx) mRNA abundance was observed in senescent cells. No other changes in the activities or mRNA abundances of any of the antioxidant defenses were observed in early and late passage cultures. The relationships between oxidant generation, mitochondrial enzyme activities, and antioxidant defense observed during proliferative senescence are dissimilar to those detected between fetal and postnatal fibroblasts as well as those found between fibroblast lines obtained from young and old individuals. The relevance of the differences between these models is discussed.

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The mitochondrial electron transfer alteration as a factor involved in the brain aging

Cited by 128 publications

References 51 publications

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Development and Age-associated Differences in Electron Transport Potential and Consequences for Oxidant Generation

Differences in electron transport potential, antioxidant defenses, and oxidant generation in young and senescent fetal lung fibroblasts (WI-38)

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