Antioxidant agents have a different expression pattern in muscle fibers of patients with mitochondrial diseases

Filosto, Massimiliano; Tonin, Paola; Vattemi, Gaetano; Spagnolo, Michele; Rizzuto, Nicolo’; Tomelleri, Giuliano

doi:10.1007/s004010100455

Cited by 36 publications

(23 citation statements)

References 22 publications

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“…Histochemical and immunohistochemical studies on muscle biopsies have shown that mitochondrial disorders caused by point mutations or deletions in mtDNA lead to an induction of antioxidant enzymes, possibly to counter chronic oxidative stress (16). Our study further supports the hypotheses that (i) mitochondrial diseases are associated with chronic oxidative stress and (ii) systemic levels of oxidative stress are reflected in peripheral blood GSH levels, making such measurements a potentially useful and non-invasive assay to routinely monitor redox imbalance.…”

Section: Discussionsupporting

confidence: 73%

“…Numerous in vitro studies have shown that inhibition of respiratory chain complexes results in elevated levels of ROS within the mitochondrial matrix, ultimately leading to oxidative stress (15). These reports are supported by studies documenting increased production of ROS, decreased GSH, a compensatory increase in antioxidant enzymes, and elevated lipid hydroperoxide levels in blood and biopsy samples from a variety of mitochondrial disorders (10,16,17). Two reports on chronic progressive external ophthalmoplegia (CPEO) demonstrated low GSH levels in plasma and erythrocytes, higher levels of ROS, and a compensatory increase in antioxidant enzyme in muscle fibroblasts (10,17).…”

Section: Discussionmentioning

confidence: 53%

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Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia

Atkuri

Cowan

Kwan

et al. 2009

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

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Disorders affecting mitochondria, including those that directly affect the respiratory chain function or result from abnormalities in branched amino acid metabolism (organic acidemias), have been shown to be associated with impaired redox balance. Almost all of the evidence underlying this conclusion has been obtained from studies on patient biopsies or animal models. Since the glutathione (iGSH) system provides the main protection against oxidative damage, we hypothesized that untreated oxidative stress in individuals with mitochondrial dysfunction would result in chronic iGSH deficiency. We confirm this hypothesis here in studies using high-dimensional flow cytometry (Hi-D FACS) and biochemical analysis of freshly obtained blood samples from patients with mitochondrial disorders or organic acidemias. T lymphocyte subsets, monocytes and neutrophils from organic acidemia and mitochondrial patients who were not on antioxidant supplements showed low iGSH levels, whereas similar subjects on antioxidant supplements showed normal iGSH. Measures of iROS levels in blood were insufficient to reveal the chronic oxidative stress in untreated patients. Patients with organic acidemias showed elevated plasma protein carbonyls, while plasma samples from all patients tested showed hypocitrullinemia. These findings indicate that measurements of iGSH in leukocytes may be a particularly useful biomarker to detect redox imbalance in mitochondrial disorders and organic acidemias, thus providing a relatively noninvasive means to monitor disease status and response to therapies. Furthermore, studies here suggest that antioxidant therapy may be useful for relieving the chronic oxidative stress that otherwise occurs in patients with mitochondrial dysfunction. organic acidemia ͉ mitochondrial disorders

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 53%

Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia

Atkuri

Cowan

Kwan

et al. 2009

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

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“…Nevertheless, markers of increased ROS have been found in muscle biopsies from patients with mitochondrial disease (48)(49)(50). It is clear that elevated ROS are injurious to mitochondria.…”

Section: Cell Death In Mitochondrial and In Neurodegenerative Diseasementioning

confidence: 99%

Neuronal degeneration and mitochondrial dysfunction

Schon¹,

Manfredi²

2003

J. Clin. Invest.

264

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Over the last decade, the underlying genetic bases of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, and rare familial forms of Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS), have been identified. However, the etiologies of sporadic AD, PD, and ALS, which are among the most common neurodegenerative diseases, are still unclear, as are the pathogenic mechanisms giving rise to the various, and often highly stereotypical, clinical features of these diseases. Despite the differential clinical features of the various neurodegenerative disorders, the fact that neurons are highly dependent on oxidative energy metabolism has suggested a unified pathogenetic mechanism of neurodegeneration, based on an underlying dysfunction in mitochondrial energy metabolism.Mitochondria are the seat of a number of important cellular functions, including essential pathways of intermediate metabolism, amino acid biosynthesis, fatty acid oxidation, steroid metabolism, and apoptosis. Of key importance to our discussion here is the role of mitochondria in oxidative energy metabolism. Oxidative phosphorylation (OXPHOS) generates most of the cell's ATP, and any impairment of the organelle's ability to produce energy can have catastrophic consequences, not only due to the primary loss of ATP, but also due to indirect impairment of "downstream" functions, such as the maintenance of organellar and cellular calcium homeostasis. Moreover, deficient mitochondrial metabolism may generate reactive oxygen species (ROS) that can wreak havoc in the cell. It is for these reasons that mitochondrial dysfunction is such an attractive candidate for an "executioner's" role in neuronal degeneration.The mitochondrion is the only organelle in the cell, aside from the nucleus, that contains its own genome and genetic machinery. The human mitochondrial genome (1) is a tiny 16.6-kb circle of double-stranded mitochondrial DNA (mtDNA) (Figure 1). It encodes 13 polypeptides, all of which are components of the respiratory chain/OXPHOS system, plus 24 genes, specifying two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs), that are required to synthesize the 13 polypeptides. Obviously, an organelle as complex as a mitochondrion requires more than 37 gene products; in fact, about 850 polypeptides, all encoded by nuclear DNA (nDNA), are required to build and maintain a functioning organelle. These proteins are synthesized in the cytoplasm and are imported into the organelle, where they are partitioned into the mitochondrion's four main compartments -the outer mitochondrial membrane (OMM), the inner mitochondrial membrane (IMM), the intermembrane space (IMS), and the matrix, located in the interior (the organelle's "cytoplasm"). Of the 850 proteins, approximately 75 are structural components of the respiratory complexes ( Figure 2) and at least another 20 are required to assemble and maintain them in working order. The five complexes of the respiratory chain...

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“…The overexpression of MnSOD is probably due to a compensatory mechanism that counteracts the consequences of elevated ROS, as reported in other disorders. [58][59][60][61] In general, the cblC fibroblasts had the highest intracellular ROS content of all these patient-derived fibroblasts. 28 In addition, the examination of F-2 isoprostanes and dityrosine as markers of oxidative damage showed that patients with cblC disorder consistently had the highest levels of oxidative damage in urinary oxidative stress profiling.…”

Section: Pathophysiology Of Remethylation Disordersmentioning

confidence: 97%

Isolated and Combined Remethylation Disorders

Richard

Brasil

Leal

et al. 2017

Journal of Inborn Errors of Metabolism and Screening

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Genetic defects affecting the remethylation pathway cause hyperhomocysteinemia. Isolated remethylation defects are caused by mutations of the 5, 10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), methionine synthase (MTR), and MMADHC genes, and combined remethylation defects are the result of mutations in genes involved in the synthesis of either methylcobalamin or adenosylcobalamin, that is, the active cofactors of MTRR and methylmalonyl-CoA mutase. Diagnosis is based on the biochemical analysis of amino acids, homocysteine, propionylcarnitine, methylmalonic acid, S-adenosylmethionine, and 5-methylentetrahydrofolate in physiological fluids. Gene-by-gene Sanger sequencing has long been the gold standard genetic analysis for confirming the disorder and identifying the gene involved, but massive parallel sequencing is now being used to examine all those potentially involved in one go. Early treatment to rescue metabolic homeostasis is based on the following of an appropriate diet, betaine administration, and, in some cases, oral or intramuscular administration of vitamin B 12 or folate. Elevated ROS levels, apoptosis, endoplasmic reticulum (ER) stress, the activation of autophagy, and alterations in Ca 2þ homeostasis may all contribute toward the pathogenesis of the disease. Pharmacological agents to restore the function of the ER and mitochondria and/or to reduce oxidative stress-induced apoptosis might provide novel ways of treating patients with remethylation disorders.

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Antioxidant agents have a different expression pattern in muscle fibers of patients with mitochondrial diseases

Cited by 36 publications

References 22 publications

Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia

Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia

Neuronal degeneration and mitochondrial dysfunction

Isolated and Combined Remethylation Disorders

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