Selective Inactivation of α-Ketoglutarate Dehydrogenase and Pyruvate Dehydrogenase:  Reaction of Lipoic Acid with 4-Hydroxy-2-nonenal

Humphries, Kenneth M.; Szweda, Luke I.

doi:10.1021/bi981512h

Cited by 322 publications

(245 citation statements)

References 51 publications

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“…These findings indicate vulnerable neurons in AD have increased mitochondrial degradation products, suggesting either greater turnover of mitochondria by autophagy or a reduction of proteolytic turnover leading to accumulation of mtDNA and mitochondrial protein. These mitochondrial components are likely damaged, because hydroxynonenal adducts to lipoic acid (Humphries and Szweda, 1998), the prosthetic group of two key Krebs cycle enzymes, can be found in the same vacuoles substantiates the view that these components are nonfunctional (G. Perry, M. A. Smith, and L. Szweda, unpublished observations). Also, because cytochrome oxidase must be membrane-bound to function, our findings are consistent with the low functional activity of many mitochondrial enzymes in AD (Wong-Riley et al, 1997).…”

Section: Discussionsupporting

confidence: 57%

Mitochondrial Abnormalities in Alzheimer's Disease

Aliev²,

et al. 2001

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The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we usedin situhybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

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Section: Discussionsupporting

confidence: 57%

Mitochondrial Abnormalities in Alzheimer's Disease

Aliev²,

et al. 2001

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“…Supplementation with LA may replenish needed cofactors for α-keto acid dehydrogenases (pyruvate oxidoreductase and 2-oxo-glutarate oxidoreductase) used in pyruvate and fatty acid metabolism. It has been shown that the proportion of the active form of pyruvate oxidoreductase declines with age (25), possibly due to modification of the lipoamide moiety of the E2 subunit (26). Thus, feeding old rats LA may reverse the age-associated decline in LA-dependent oxidoreductase activity.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

et al. 2001

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Oxidative stress has been implicated as a causal factor in the aging process of the heart and other tissues. To determine the extent of age-related myocardial oxidative stress, oxidant production, antioxidant status, and oxidative DNA damage were measured in hearts of young (2 months) and old (28 months) male Fischer 344 rats. Cardiac myocytes isolated from old rats showed a nearly threefold increase in the rate of oxidant production compared to young rats, as measured by the rates of 2,7-dichlorofluorescin diacetate oxidation. Determination of myocardial antioxidant status revealed a significant twofold decline in the levels of ascorbic acid (P = 0.03), but not α-tocopherol. A significant age-related increase (P = 0.05) in steady-state levels of oxidative DNA damage was observed, as monitored by 8-oxo-2′-deoxyguanosine levels. To investigate whether dietary supplementation with (R)-α-lipoic acid (LA) was effective at reducing oxidative stress, young and old rats were fed an AIN-93M diet with or without 0.2% (w/w) LA for 2 wk before death. Cardiac myocytes from old, LA-supplemented rats exhibited a markedly lower rate of oxidant production that was no longer significantly different from that in cells from unsupplemented, young rats. Lipoic acid supplementation also restored myocardial ascorbic acid levels and reduced oxidative DNA damage. Our data indicate that the aging rat heart is under increased mitochondrial-induced oxidative stress, which is significantly attenuated by lipoic acid supplementation. Keywordsaging; cardiac myocytes; oxidative stress; lipoic acid Aging is associated with an increased incidence of cardiac arrhythmias and diastolic and systolic dysfunction, which may ultimately lead to heart failure. Heart failure alone is the leading cause of hospitalization, permanent disability, and death in persons over the age of HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript 65 (1) in the U.S. Because of the enormous suffering and health care burden that cardiac dysfunction causes, much effort has gone into understanding the mechanisms leading to agerelated myocardial decline. It has been difficult, however, to separate the effects of aging per se from those of age-associated diseases (atherosclerosis, diabetes, hypertension) on cardiac performance. Thus, the relative contribution of 'aging' to myocardial dysfunction is not well defined.Even though the mechanisms leading to alterations in cardiac performance are not well understood, there is reason to suspect increased oxidative stress to significantly contribute to myocardial dysfunction with age. It is generally agreed that isolated mitochondrial preparations from old compared to young hearts produce more reactive oxygen species (ROS), reflecting an age-related decline in coupling of electron transport to ATP production. These changes in mitochondria may lead to the reported increase in superoxide and hydrogen peroxide production in mitochondria prepared from old vs. young rats (2-4). Thus, it is conceiv...

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“…HNE is a reactive aldehyde that originates from the peroxidation of membranes and forms a mixture of adduct types on the side-chains of cysteine, lysine, and histidine through a Michael-type nucleophilic addition (Davies and Dean, 1997). The protein modifications, HNE (Humphries and Szweda, 1998) and nitrotyrosine (Viner et al, 1999), have been shown to inhibit protein function. The levels of these two markers of oxidative stress, 3NT and HNE, on myosin and actin did not increase with age .…”

Section: Aging and Oxidative Modifications Of Actin And Myosinmentioning

confidence: 99%

Age-related muscle dysfunction

Thompson

2009

Experimental Gerontology

193

163

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Aging is associated with a progressive decline of muscle mass, strength, and quality, a condition described as sarcopenia of aging. Despite the significance of skeletal muscle atrophy, the mechanisms responsible for the deterioration of muscle performance are only partially understood. The purpose of this review is to highlight cellular, molecular and biochemical changes that contribute to age-related muscle weakness. Keywordsactin; myosin; aged muscle; enzymatic activity; oxidative modifications SarcopeniaAging is associated with a progressive decline of muscle mass, strength, and quality, a condition described as sarcopenia. These age-related changes are observed in healthy, active adults who are 50 years and older (Hughes et al., 2002). The prevalence of sarcopenia in older adults under the age of 70 years is about 25% and increases to 40% in adults 80 years or older (Baumgartner et al., 1998). Sarcopenia represents a risk factor for frailty, loss of independence, and physical disability (Roubenoff, 2000). Loss of mobility resulting from muscle loss predicts major physical disability and mortality, and is associated with poor quality of life, social needs, and health care needs (Fried and Guralnik, 1997). The economic impact of sarcopenia and its detrimental correlates are immense (Janssen et al., 2004). Thus, understanding the mechanisms leading to muscle dysfunction (e.g., weakness) at advanced age represents a high public health priority. The purpose of this article is to highlight cellular, molecular, and biochemical changes that contribute to age-related muscle dysfunction. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Muscle physiology-short reviewFor skeletal muscle, the control of force has to be accurate and precise with the contractile machinery being switched on and off rapidly to allow for complex coordinated movements. Action potentials initiated at the neuromuscular junction propagate along the length of the fiber and the transverse tubules. As the wave of depolarization passes down the transverse tubules there is an interaction with the sarcoplasmic reticulum that results in the release of calcium, initiating the interaction of actin and myosin and muscle contraction. This process is known as excitation-contraction coupling. Thus, age-related structural changes or chemical modifications in proteins that affect excitation-contraction coupling are likely to influence muscle function.The basic contractile unit of muscle, the myofibril, consists of a linear array of sarcomeres, which contains interdigitating myosin and actin fila...

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Selective Inactivation of α-Ketoglutarate Dehydrogenase and Pyruvate Dehydrogenase: Reaction of Lipoic Acid with 4-Hydroxy-2-nonenal

Cited by 322 publications

References 51 publications

Mitochondrial Abnormalities in Alzheimer's Disease

Mitochondrial Abnormalities in Alzheimer's Disease

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

Age-related muscle dysfunction

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