Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

Ristow, Michael; Pfister, M.; Yee, Andrew J.; Schubert, Markus; Michael, Laura; Zhang, Chenyu; Ueki, Kojhiro; Michael, M. Dodson; Lowell, Bradford B.; Kahn, C. Ronald

doi:10.1073/pnas.220403797

Cited by 211 publications

(172 citation statements)

References 59 publications

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“…33) Oxidative stress is caused by an imbalance in pro-oxidants and antioxidants, which cause a depletion or inactivation of the antioxidant in hepatocytes, ultimately leading to necrosis and/or apoptosis. 34,35) MDA is an indicator of oxidative stress and a major by-product resulting from lipid peroxidation. In addition, SOD, GSH-Px, GSH-Rd and catalase are the enzymes for which reduced activity is associated with the accumulation of reactive free radicals, leading to deleterious effects.…”

Section: Discussionmentioning

confidence: 99%

Retraction: Asiatic Acid from Potentilla chinensis Attenuate Ethanol-Induced Hepatic Injury via Suppression of Oxidative Stress and Kupffer Cell Activation

Wei

Huang

et al. 2013

Biological & Pharmaceutical Bulletin

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This study examined the effect of Asiatic acid from Potentilla chinensis (AAPC) on chronic ethanolinduced hepatic injury. Rats underwent intragastric administration of ethanol (5.0-9.0 g/kg) once a day for 12 weeks. A subset of rats were also intragastrically treated with AAPC (2, 4 or 8 mg/kg) once a day. In the end, AAPC treatment significantly protected against ethanol-induced liver injury, as evidenced by the decrease in serum alanine and aspartate aminotransferases levels and the attenuation of histopathological changes in rats. Additionally, AAPC significantly decreased blood alcohol and acetaldehyde concentrations by enhancing alcohol dehydrogenase and aldehyde dehydrogenase activities. Mechanistically, studies showed that AAPC remarkably alleviated the formations of malondialdehyde and myeloperoxidase, restored impaired antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase, and inhibited cytochrome P450 (CYP)2E1 activity. Moreover, the over-expression of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), the elevated plasma endotoxin level and the up-regulated Toll-like receptor 4 (TLR4), CD14 and myeloid differentiation factor 88 (MyD88) as well as nuclear factor-κB were also suppressed by AAPC in ethanol-intoxicated rats. In conclusion, the protective effect of AAPC on ethanol-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress and inhibit Kupffer cell activation by decreasing the level of plasma endotoxin and the expression of TLR4, CD14 and MyD88.

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Section: Discussionmentioning

confidence: 99%

Retraction: Asiatic Acid from Potentilla chinensis Attenuate Ethanol-Induced Hepatic Injury via Suppression of Oxidative Stress and Kupffer Cell Activation

Wei

Huang

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Frataxin-deficient cells are impaired in oxidative phosphorylation (36), and there are several possible causes of this defect, including insufficient available inorganic phosphate.…”

Section: Physiological Implications Of Iron Accumulation and Precipitmentioning

confidence: 99%

Co-precipitation of Phosphate and Iron Limits Mitochondrial Phosphate Availability in Saccharomyces cerevisiae Lacking the Yeast Frataxin Homologue (YFH1)

Seguin

Santos

Pain

et al. 2011

Journal of Biological Chemistry

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Saccharomyces cerevisiae cells lacking the yeast frataxin homologue (⌬yfh1) accumulate iron in the mitochondria in the form of nanoparticles of ferric phosphate. The phosphate content of ⌬yfh1 mitochondria was higher than that of wild-type mitochondria, but the proportion of mitochondrial phosphate that was soluble was much lower in ⌬yfh1 cells. The rates of phosphate and iron uptake in vitro by isolated mitochondria were higher for ⌬yfh1 than wild-type mitochondria, and a significant proportion of the phosphate and iron rapidly became insoluble in the mitochondrial matrix, suggesting co-precipitation of these species after oxidation of iron by oxygen. Increasing the amount of phosphate in the medium decreased the amount of iron accumulated by ⌬yfh1 cells and improved their growth in an iron-dependent manner, and this effect was mostly transcriptional. Overexpressing the major mitochondrial phosphate carrier, MIR1, slightly increased the concentration of soluble mitochondrial phosphate and significantly improved various mitochondrial functions (cytochromes, [Fe-S] clusters, and respiration) in ⌬yfh1 cells. We conclude that in ⌬yfh1 cells, soluble phosphate is limiting, due to its coprecipitation with iron.

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“…Concurrently it was shown that frataxin promotes oxidative metabolism and ATP synthesis when overexpressed in fibroblasts (6), possibly by a direct interaction with the respiratory chain (7). Although the primary function of frataxin is still a matter of debate (8), some evidence suggests that this protein directs the intramitochondrial synthesis of Fe/S clusters (9 -12).…”

mentioning

confidence: 99%

Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth

Schulz

Thierbach

Voigt

et al. 2006

Journal of Biological Chemistry

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More than 80 years ago Otto Warburg suggested that cancer might be caused by a decrease in mitochondrial energy metabolism paralleled by an increase in glycolytic flux. In later years, it was shown that cancer cells exhibit multiple alterations in mitochondrial content, structure, function, and activity. We have stably overexpressed the Friedreich ataxia-associated protein frataxin in several colon cancer cell lines. These cells have increased oxidative metabolism, as shown by concurrent increases in aconitase activity, mitochondrial membrane potential, cellular respiration, and ATP content. Consistent with Warburg's hypothesis, we found that frataxin-overexpressing cells also have decreased growth rates and increased population doubling times, show inhibited colony formation capacity in soft agar assays, and exhibit a reduced capacity for tumor formation when injected into nude mice. Furthermore, overexpression of frataxin leads to an increased phosphorylation of the tumor suppressor p38 mitogen-activated protein kinase, as well as decreased phosphorylation of extracellular signalregulated kinase. Taken together, these results support the view that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.Friedreich ataxia is an inherited neurodegenerative disorder (1) caused by the reduced expression of mitochondrial frataxin protein (2) leading to premature death due to cardiac failure (1), diabetes mellitus and insulin resistance (3), as well as impaired ATP synthesis in humans (4, 5). Concurrently it was shown that frataxin promotes oxidative metabolism and ATP synthesis when overexpressed in fibroblasts (6), possibly by a direct interaction with the respiratory chain (7). Although the primary function of frataxin is still a matter of debate (8), some evidence suggests that this protein directs the intramitochondrial synthesis of Fe/S clusters (9 -12). Individuals suffering from Friedreich ataxia have a reduced life expectancy of 38 years on average (1) and show increased oxidative stress (13-15). Overexpression of frataxin has been shown to reduce intracellular accumulation of reactive oxygen species (ROS) 3 and to prevent menadione-induced malignant transformation of fibroblasts (16). Furthermore, disruption of the frataxin homologue in yeast has been shown to cause increased sensitivity to oxidants and promote oxidative damage to both nuclear (17), as well as mitochondrial, DNA (18). In addition, fibroblasts from Friedreich ataxia patients exhibit increased sensitivity against ionizing radiation and show an increased frequency of transforming events (19). Although malignant disease is not considered a typical feature of the disorder, Friedreich ataxia patients exhibit various types of cancer atypical for their young age (reviewed in Refs. 3 and 16). Lastly, targeted disruption of frataxin in murine hepatocytes causes decreased life span and liver tumor formation in mice. 4 In parallel to these latter findings in rodents, we questioned whether frataxin migh...

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Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

Cited by 211 publications

References 59 publications

Retraction: Asiatic Acid from <i>Potentilla chinensis</i> Attenuate Ethanol-Induced Hepatic Injury <i>via</i> Suppression of Oxidative Stress and Kupffer Cell Activation

Retraction: Asiatic Acid from <i>Potentilla chinensis</i> Attenuate Ethanol-Induced Hepatic Injury <i>via</i> Suppression of Oxidative Stress and Kupffer Cell Activation

Co-precipitation of Phosphate and Iron Limits Mitochondrial Phosphate Availability in Saccharomyces cerevisiae Lacking the Yeast Frataxin Homologue (YFH1)

Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth

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