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The redox status of cystinotic fibroblasts.

ABSTRACT: A key unresolved question in the pathogenesis of phenotype development in nephropathic cystinosis is whether intralysosomal cystine, the hallmark of this lethal inborn error of metabolism, alters cytoplasmic redox potential. Variable findings on this issue have been reported. This study of fetal and non-fetal skin and lung-derived cystinotic fibroblasts compared to origin and age-matched normal control fibroblasts reveals that cystinotic cells do not exhibit redox perturbations. We find that the steady-state redox status as assessed by the [GSH]/[GSSG] ratio, an indicator of the intracellular redox poise, is unchanged in cystinotic cells. Furthermore, the dependence of the intracellular GSH and cysteine pool sizes and the [GSH]/[GSSG] ratio are similarly dependent on the two major sources of cysteine, i.e. the transsulfuration pathway and the plasma membrane cystine transporter, xc(-), in both cystinotic and control cells, and the presence of lysosomal cystine has no measurable effect on the redox status of these cells. Hence, mechanisms other than cytosolic redox perturbations are involved in the etiology of nephropathic cystinosis.

SUBMITTER: Vitvitsky V

PROVIDER: S-EPMC2839033 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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The redox status of cystinotic fibroblasts.

Vitvitsky Victor V Witcher Marc M Banerjee Ruma R Thoene Jess J

Molecular genetics and metabolism 20091221 4

A key unresolved question in the pathogenesis of phenotype development in nephropathic cystinosis is whether intralysosomal cystine, the hallmark of this lethal inborn error of metabolism, alters cytoplasmic redox potential. Variable findings on this issue have been reported. This study of fetal and non-fetal skin and lung-derived cystinotic fibroblasts compared to origin and age-matched normal control fibroblasts reveals that cystinotic cells do not exhibit redox perturbations. We find that the ...[more]

PMID: 20061170

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Project description:OBJECTIVES:Redox regulation plays a crucial role in balancing the cardiovascular system. In this prospective study we aimed to identify currently unknown correlations valuable to cardiovascular research and patient management. METHODS:Blood samples from 500 patients were collected directly before cardiosurgical interventions (Ethics Committee reference number 85/11). Four central redox parameters were determined together with about 30 clinical, anthropometric, and metabolic parameters. RESULTS:Creatinine levels and pulmonary hypertension were significant predictors of the total antioxidant status (TAOS) in the patients; total glutathione levels were linked to C-peptide, and creatinine, gender, and ventricular arrhythmia influenced nitrate/nitrite levels. Notably, significant interactions were found between medication and redox parameters. Calcium channel blockers (CCBs) were positive predictors of total glutathione levels, whereas angiotensin-converting enzyme inhibitors and CCBs were negative predictors of NOx levels. Age showed the highest correlation with the duration of the intensive care stay, followed by NOx levels, creatinine, TAOS, and C-reactive protein. DISCUSSION:In this prospective study we determined multiple correlations between redox markers and parameters linked to cardiovascular diseases. The data point towards so far unknown interdependencies, particularly between antihypertensive drugs and redox metabolism. A thorough follow-up to these data has the potential to improve patient management. ABBREVIATIONS:A: absorption; ?A: absorption difference; ABTS: 2,2'-azino-di(3-ethylbenzothiazoline sulfonate); ACE: angiotensin-converting enzyme; AO: antioxidant; ARB: angiotensin receptor blocker; BMI: body mass index; CAD: coronary artery disease; CCB: calcium channel blocker; CDC: coronary heart diseases; COPD: chronic obstructive pulmonary disease; CRP: C-reactive protein; CVD: cardiovascular diseases; Cu-OOH: cumene hydroperoxide; D: dilution factor; DAN: 2,3-diaminonaphtalene; DMSO: dimethylsulfoxide; DNA: deoxyribonucleic acid; DTNB: 5,5-dithiobis(2-nitrobenzoate); ?: extinction coefficient; EDRF: endothelium-derived relaxing factor; fc: final concentration; GPx: glutathione peroxidases; (h)GR: (human) glutathione reductase; GSH: (reduced) glutathione; GSSG: glutathione disulfide; GST: glutathione-S-transferase; Hb: hemoglobin; HDL: high-density lipoprotein; Hk: hematocrit; H2O2: hydrogen peroxide; ICS: intensive care stay; LDH: lactate dehydrogenase; LDL: low-density lipoprotein; MI: myocardial infarction; NED: N-(1-naphthyl)-ethylendiamine-dihydrochloride; NOS: nitric oxide synthase; NOx: nitrate/nitrite; NR: nitrate reductase; PBS: phosphate buffered saline; PCA: principle component analysis; PH: pulmonary hypertension; ROS: reactive oxygen species; RNS: reactive nitrogen species; RT: room temperature (25°C); SA: sulfanilamide; SOD: superoxide dismutase; SSA: sulfosalicylic acid; TAC: total antioxidant capacity; TAOS: total antioxidant status; TEAC: trolox equivalent antioxidative capacity; TG: triglycerides; tGSH: total glutathione; TNB-: 2-nitro-5-thiobenzoate; U: unit; UV: ultraviolet; VA: volume activity; Wc: working concentration; WHR: waist-hip ratio.

Project description:Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

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The redox status of cystinotic fibroblasts.

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The redox status of cystinotic fibroblasts.

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