The sites and topology of mitochondrial superoxide production

Brand, Martin D.

doi:10.1016/j.exger.2010.01.003

Cited by 970 publications

(776 citation statements)

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“…In this context, an interesting relationship was found between the rate of ROS production during mitochondrial reverse electron transport in vitro and lifespan in vertebrate homeotherms (Lambert et al., 2007). Several reviews have described the mechanisms of ROS production in mitochondria and discussed their potential contribution in aging (Balaban et al., 2005; Brand, 2010). Here, we will only give a brief summary and we will focus on the possible link between ROS production and mPTP opening during aging.…”

Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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“…There are currently seven separate sites of mammalian mitochondrial ROS production that have been identified and characterized [4]. Importantly, because H 2 O 2 is relatively stable and membrane-permeable, it can diffuse out of the mitochondria into the cytoplasm [5].…”

Section: Ros Production Antioxidant Defences and Oxidative Stressmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

495

347

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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“…38,50 Proteins identified as strongly oxidized in this study present several characteristics which are typical of proteins subjected to carbonylation: clearly, the proteins are located in mitochondria that are an important source of ROS generation; furthermore, several of them have a metal ion in the protein structure (aconitate hydratase, has an iron−sulfur cluster; cytochrome b-c1 subunit has a zinc binding site) and/ or are localized in proximity of ROS generation sites, especially represented by complex I (that releases superoxide in the matrix) and complex III (that releases superoxide both in the matrix and in the intermembrane space). 5 In fact, complex I was found associated with several mitochondrial dehydrogenases, including 2-oxoglutarate dehydrogenase complex and mitochondrial malate dehydrogenase (both found as carbonylated in this study). 51 Interestingly, two enzymes found strongly oxidized in this study (2-oxoglutarate dehydrogenase and pyruvate dehydrogenase complex) are themselves sites of ROS production.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 95%

“…This enzyme has an iron−sulfur cluster that is vulnerable to ROS attack, a structural characteristic that has led to its use as an indicator of superoxide production. 5 Oxidation of this protein occurs mostly at the C-terminal of the proteins, where the binding sites for the iron−sulfur cluster and for the substrate are located ( Figure 3S). Furthermore, when its FeS center is oxidized by superoxide, Fe 3+ is released and this unprotected, free iron ion can trigger a Fenton reaction causing damage to proteins in its proximity.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 99%

Profiling Carbonylated Proteins in Heart and Skeletal Muscle Mitochondria from Trained and Untrained Mice

Carpentieri¹,

Gamberi

Modesti

et al. 2016

J. Proteome Res.

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Understanding the relationship between physical exercise, reactive oxygen species, and skeletal muscle modification is important in order to better identify the benefits or the damages that appropriate or inappropriate exercise can induce. Heart and skeletal muscles have a high density of mitochondria with robust energetic demands, and mitochondria plasticity has an important role in both the cardiovascular system and skeletal muscle responses. The aim of this study was to investigate the influence of regular physical activity on the oxidation profiles of mitochondrial proteins from heart and tibialis anterior muscles. To this end, we used the mouse as animal model. Mice were divided into two groups: untrained and regularly trained. The carbonylated protein pattern was studied by two-dimensional gel electrophoresis followed by Western blot with anti-dinitrophenyl hydrazone antibodies. Mass spectrometry analysis allowed the identification of several different protein oxidation sites, including methionine, cysteine, proline, and leucine residues. A large number of oxidized proteins were found in both untrained and trained animals. Moreover, mitochondria from skeletal muscles and heart showed almost the same carbonylation pattern. Interestingly, exercise training seems to increase the carbonylation level mainly of mitochondrial proteins from skeletal muscle.

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The sites and topology of mitochondrial superoxide production

Cited by 970 publications

References 113 publications

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria and aging: A role for the mitochondrial transition pore?

Taking a “good” look at free radicals in the aging process

Profiling Carbonylated Proteins in Heart and Skeletal Muscle Mitochondria from Trained and Untrained Mice

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