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Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells.

ABSTRACT: Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.

SUBMITTER: Khdour OM

PROVIDER: S-EPMC6148561 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells.

Khdour Omar M OM Bandyopadhyay Indrajit I Visavadiya Nishant P NP Roy Chowdhury Sandipan S Hecht Sidney M SM

MedChemComm 20180726 9

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppress ...[more]

PMID: 30288223

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Project description:Friedreich's ataxia (FRDA) is an autosomal recessive disease caused by an intronic guanine-adenine-adenine (GAA) triplet expansion in the frataxin (FXN) gene, which leads to reduced expression of full-length frataxin (1-210) also known as isoform 1. Full-length frataxin has a mitochondrial targeting sequence, which facilitates its translocation into mitochondria where it is processed through cleavage at G41-L42 and K80-S81 by mitochondrial processing (MPP) to release mitochondrial mature frataxin (81-210). Alternative splicing of FXN also leads to expression of N-terminally acetylated extra-mitochondrial frataxin (76-210) named isoform E because it was discovered in erythrocytes. Frataxin isoforms are undetectable in serum or plasma, and originally whole blood could not be used as a biomarker in brief therapeutic trials because it is present in erythrocytes, which have a half-life of 115-days and so frataxin levels would remain unaltered. Therefore, an assay was developed for analyzing frataxin in platelets, which have a half-life of only 10-days. However, our discovery that isoform E is only present in erythrocytes, whereas, mature frataxin is present primarily in short-lived peripheral blood mononuclear cells (PBMCs), granulocytes, and platelets, meant that both proteins could be quantified in whole blood samples. We now report a quantitative assay for frataxin proteoforms in whole blood from healthy controls and FRDA patients. The assay is based on stable isotope dilution coupled with immunoprecipitation (IP) and two-dimensional-nano-ultrahigh performance liquid chromatography/parallel reaction monitoring/high resolution mass spectrometry (2D-nano-UHPLC-PRM/HRMS). The lower limit of quantification was 0.5 ng/mL for each proteoform and the assays had 100% sensitivity and specificity for discriminating between healthy controls (n = 11) and FRDA cases (N = 100 in year-1, N = 22 in year-2,3). The mean levels of mature frataxin in whole blood from healthy controls and homozygous FRDA patients were significantly different (p < 0.0001) at 7.5 ± 1.5 ng/mL and 2.1 ± 1.2 ng/mL, respectively. The mean levels of isoform E in whole blood from healthy controls and homozygous FRDA patients were significantly different (p < 0.0001) at 26.8 ± 4.1 ng/mL and 4.7 ± 3.3 ng/mL, respectively. The mean levels of total frataxin in whole blood from healthy controls and homozygous FRDA patients were significantly different (p < 0.0001) at 34.2 ± 4.3 ng/mL and 6.8 ± 4.0 ng/mL, respectively. The assay will make it possible to rigorously monitor the natural history of the disease and explore the potential role of isoform E in etiology of the disease. It will also facilitate the assessment of therapeutic interventions (including gene therapy approaches) that attempt to increase frataxin protein expression as a treatment for this devastating disease.

Dataset Information

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells.

Publications

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells.

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