Evaluation of Systemic Redox States in Patients Carrying the MELAS A3243G Mutation in Mitochondrial DNA

Ikawa, Masamichi; Arakawa, Kazuhisa; Hamano, Tadanori; Nagata, Miwako; Nakamoto, Yasunari; Kuriyama, Masaru; Koga, Yasutoshi; Yoneda, Makoto

doi:10.1159/000336568

Cited by 18 publications

(11 citation statements)

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“…Similar phenomena have also been found in patients with mitochondrial encephalomyopathy and lactic acidosis with stroke-like episodes (MELAS) [66] and Leber's hereditary optic neuropathy (LHON) [67] .…”

Section: Mitochondrial Dysfunctionsupporting

confidence: 68%

“…Studies have revealed a causal relationship between mtDNA mutations and ROS production in the affected tissues of patients with mitochondrial diseases, when the mutation load of mtDNA reaches a threshold [63,64] . For example, skin fibroblasts isolated from patients with myoclonic epilepsy with red ragged fi bers (MERRF) show enhancement of intracellular hydrogen peroxide levels and oxidative damage, and an imbalance of gene expression of antioxidant enzymes [65] .Similar phenomena have also been found in patients with mitochondrial encephalomyopathy and lactic acidosis with stroke-like episodes (MELAS) [66] and Leber's hereditary optic neuropathy (LHON) [67] . …”

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confidence: 80%

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Oxidative stress in Alzheimer’s disease

2014

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Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, infl ammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.Keywords: Alzheimer's disease; oxidative stress; β-amyloid; tau; metals; antioxidants ·Review· IntroductionThe human brain, although it constitutes only 2% of the body weight, consumes ~20% of the oxygen supplied by the respiratory system [1] . The high energy-consumption of the brain means that it is more susceptible to oxidative stress than any other organ. As the basic functional unit of the brain, the neuron is particularly vulnerable to oxidative damage because it has a higher metabolic rate than other cells [2] . The oxidation of lipids, proteins, and nucleic acids in neurons is a common pathological feature of Alzheimer's disease (AD) [3] . Neurons contain a large amount of polyunsaturated fatty acids (PUFAs) that can interact with reactive oxygen species (ROS), leading to a selfpropagating cascade of lipid peroxidation and molecular destruction [4] . Furthermore, neurons contain low levels of glutathione, an essential antioxidant for eliminating free radicals [5] . Therefore, neurons are highly susceptible to oxidative stress.An increased oxidative burden has been reported in the brains of non-demented elderly and/or sporadic AD patients [6,7] . Increased levels of oxidative stress biomarkers in the blood reflect such stress in the brain [8,9] . Currently, many blood markers of oxidative stress have been identified in AD patients or related animal models, including protein carbonyls and 3-nitrotyrosine [10,11] , , malondialdehyde (MDA) [12] , 4-hydroxynonenal (4-HNE), and F2-isoprostanes (F2-IsoPs) [13][14][15][16] . Apart from the intracellular accumulation of free radicals, changes in the activities or expressions of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, have also been described in both the central nervous system and peripheral tissues of AD patients [14,17] . Thus, oxidative stress is an important pathological feature in AD.However, how and where the oxidative stress originates in AD are open questions. Research has suggested that mitochondrial dysfunction [12,18,19] , metal accumulation [12,20,21] , hyperphosphorylated tau [22,23] , inflammation [24,25] , and β-amyloid (Aβ) accumulation [12,19] are the basic mechanisms underlying the induction of oxidative stress. Deficiency or destruction of components of the antioxidant system such as SOD in the mi...

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Section: Mitochondrial Dysfunctionsupporting

confidence: 68%

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confidence: 80%

Oxidative stress in Alzheimer’s disease

2014

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“…A recent study in 14 Japanese MELAS patients detected evidence for peripheral redox imbalance by measuring diacron-reactive oxygen metabolites and biological antioxidant potential testing. Although mutant load was not reported, the patients studied had more severe clinical symptoms than our cohort [40]. Further studies in MELAS patients with more significant clinical disease and higher levels of mutant load in peripheral blood would be needed in order to study the potential relationship between mutant load and redox status in more detail.…”

Section: Discussionmentioning

confidence: 83%

Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status

Enns

Moore

et al. 2014

PLoS ONE

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Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential −251 mV±9.7, p<0.0001) with an increased level of oxidation by ∼9 mV compared to controls (−260 mV±6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at −242 mV±7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.

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“…Cytoplasmic hybrids (cybrids) harboring the A8344G mutation exhibit decreased efficiency of ATP synthesis in mitochondria and become more sensitive to extrinsic oxidative stress such as hydrogen peroxide and UV irradiation [24–26] and the skin fibroblasts from MERRF patients demonstrate higher intracellular hydrogen peroxide levels and increased oxidative damage to the mitochondrial proteins containing iron–sulfur along with imbalance in the gene expression of antioxidant enzymes [27]. Human MELAS (mitochondrial encephalomyopathy and lactic acidosis with stroke-like episodes) patients carrying the A3243G mutation of mtDNA demonstrated increased oxidative stress systemically [28]. Leber’s hereditary optic neuropathy (LHON) results from one of three point mutations in mtDNA coding for complex I components and LHON cybrids have increased superoxide production compared to wild-type cells [29].…”

Section: Mitochondrial Dna and Oxidative Stressmentioning

confidence: 99%

Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease

Yan¹,

Wang

Zhu

2013

Free Radical Biology and Medicine

635

397

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Alzheimer disease (AD) and Parkinson disease (PD) are the two most common age-related neurodegenerative diseases characterized by prominent neurodegeneration in selective neural systems. Although a small fraction of AD and PD cases exhibit evidence of heritability, among which many genes have been identified, the majority are sporadic without known causes. Molecular mechanisms underlying neurodegeneration and pathogenesis of these diseases remain elusive. Convincing evidence demonstrates oxidative stress as a prominent feature in AD and PD and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD. Notably, mitochondrial dysfunction is also a prominent feature in these diseases, which is likely to be of critical importance in the genesis and amplification of reactive oxygen species and the pathophysiology of these diseases. In this review, we focus on changes in mitochondrial DNA and mitochondrial dynamics, two aspects critical to the maintenance of mitochondrial homeostasis and function, in relationship with oxidative stress in the pathogenesis of AD and PD.

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Evaluation of Systemic Redox States in Patients Carrying the MELAS A3243G Mutation in Mitochondrial DNA

Cited by 18 publications

References 43 publications

Oxidative stress in Alzheimer’s disease

Oxidative stress in Alzheimer’s disease

Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status

Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease

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