Ageing, oxidative stress, and mitochondrial uncoupling

Harper, Mary‐Ellen; Bevilacqua, Lisa; Hagopian, Kevork; Weindruch, Richard; Ramsey, Jon J.

doi:10.1111/j.1365-201x.2004.01370.x

Cited by 221 publications

(152 citation statements)

References 97 publications

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“…Two correlated features linked to the mitochondrial electron transport chain are extended life spans and greatly enlarged brains. Considerable evidence (48,49) has aging and diseases of old age associated with damage from mitochondrial-generated radical species, i.e., delaying the onset of excessive damage should extend life spans. A possibility worth exploring is that an effect of the marked changes in the electron transport chain proteins of anthropoids was to reduce the radical flux which accompanies oxidative energy production.…”

Section: Discussionmentioning

confidence: 99%

Rapid electrostatic evolution at the binding site for cytochrome c on cytochrome c oxidase in anthropoid primates

Schmidt

Wildman

Uddin

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome c (CYC) oxidase (COX), a multisubunit enzyme that functions in mitochondrial aerobic energy production, catalyzes the transfer of electrons from CYC to oxygen and participates in creating the electrochemical gradient used for ATP synthesis. Modeling three-dimensional structural data on COX and CYC reveals that 57 of the >1,500 COX residues can be implicated in binding CYC. Because of the functional importance of the transfer of electrons to oxygen, it might be expected that natural selection would drastically constrain amino acid replacement rates of CYC and COX. Instead, in anthropoid primates, although not in other mammals, CYC and COX show markedly accelerated amino acid replacement rates, with the COX acceleration being much greater at the positions that bind CYC than at those that do not. Specifically, in the anthropoid lineage descending from the last common ancestor of haplorhines (tarsiers and anthropoids) to that of anthropoids (New World monkeys and catarrhines) and that of catarrhines (Old World monkeys and apes, including humans), a minimum of 27 of the 57 COX amino acid residues that bind CYC were replaced, most frequently from electrostatically charged to noncharged residues. Of the COX charge-bearing residues involved in binding CYC, half (11 of 22) have been replaced with uncharged residues. CYC residues that interact with COX residues also frequently changed, but only two of the CYC changes altered charge. We suggest that reducing the electrostatic interaction between COX and CYC was part of the adaptive evolution underlying the emergence of anthropoid primates. mitochondria ͉ electron transport chain ͉ molecular coevolution C ytochrome c (CYC) and the subunits of CYC oxidase (COX) are mitochondrial-functioning proteins that play a central role in aerobic energy production. By catalyzing the transfer of electrons from CYC to oxygen, COX greatly increases an electrochemical gradient used for ATP synthesis. As a consequence of their critical function, mutations altering the structures of either CYC or COX must face the close scrutiny of natural selection. Among vertebrates, relatively few amino acid replacements have occurred in the structures of CYC and COX. However, against this background of slow rates of CYC and COX evolution, upsurges in COX and CYC amino acid replacement rates occurred during the emergence and evolution of the larger brained primates (members of Anthropoidea) (1-12). Here, by using atomic resolution structural data on bovine COX (13) and horse CYC (14) and an experimentally verified model of the interaction between COX and CYC (15, 16), we identify, among the Ͼ1,500 amino acid residues of COX, 57 residues that are likely to bind CYC during delivery of electrons to oxygen. We then demonstrate that the amino acid replacement rate acceleration in anthropoid lineages is especially pronounced in the subset of COX residues that can bind CYC. We further demonstrate that, among these CYC-binding COX residues, many amino acid replacements were from charge-bearing [electros...

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Section: Discussionmentioning

confidence: 99%

Rapid electrostatic evolution at the binding site for cytochrome c on cytochrome c oxidase in anthropoid primates

Schmidt

Wildman

Uddin

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…It is the only organelle apart from the nucleus to contain its own DNA, mtDNA is a circular molecule of just over 16000 base pairs making up 37 genes that encode 13 components of the electron transport chain, and transcription and translational machinery. Oxidation of fuels, such as glucose, generates reducing equivalents that feed into the electron transport chain of the mitochondria (Harper et al, 2004). The electron transport chain generates ATP by oxidative phosphorylation, creating a proton gradient through sequential transfer of electrons donated by reducing equivalents.…”

Section: Mitochondria and Rosmentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

159

140

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Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O 2 -) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (OONO -). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr)

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“…In these examples, ROS act locally as toxin and distantly as signaling molecules. However, it appears that ROS have a number of other potential biochemical functions such as biochemical signaling, gene expression, protein inhibition, environmental sensing, and activation of transcription factors (4)(5)(6)(7)11).…”

Section: Oxygen: a Gas To Love And Fearmentioning

confidence: 99%