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

Omar Khdour, Indrajit Bandyopadhyay, Nishant P. Visavadiya, Sandipan Roy Chowdhury, Sidney Hecht

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1491-1501
Number of pages11
JournalMedChemComm
Volume9
Issue number9
DOIs
StatePublished - Jan 1 2018

Fingerprint

Friedreich Ataxia
Organelle Biogenesis
Antioxidants
Methylene Blue
Substitution reactions
Neurodegenerative diseases
Aconitate Hydratase
Derivatives
Gene encoding
Mitochondrial Membrane Potential
Mitochondrial Proteins
Essential Genes
Cytotoxicity
Neurodegenerative Diseases
Disease Progression
phenothiazine
frataxin
Adenosine Triphosphate
Maintenance
methylene violet

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells. / Khdour, Omar; Bandyopadhyay, Indrajit; Visavadiya, Nishant P.; Roy Chowdhury, Sandipan; Hecht, Sidney.

In: MedChemComm, Vol. 9, No. 9, 01.01.2018, p. 1491-1501.

Research output: Contribution to journalArticle

Khdour, Omar ; Bandyopadhyay, Indrajit ; Visavadiya, Nishant P. ; Roy Chowdhury, Sandipan ; Hecht, Sidney. / Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells. In: MedChemComm. 2018 ; Vol. 9, No. 9. pp. 1491-1501.
@article{b996426222c348ce83e6e5b6fc255865,
title = "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.",
author = "Omar Khdour and Indrajit Bandyopadhyay and Visavadiya, {Nishant P.} and {Roy Chowdhury}, Sandipan and Sidney Hecht",
year = "2018",
month = "1",
day = "1",
doi = "10.1039/c8md00274f",
language = "English (US)",
volume = "9",
pages = "1491--1501",
journal = "MedChemComm",
issn = "2040-2503",
publisher = "Royal Society of Chemistry",
number = "9",

}

TY - JOUR

T1 - Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells

AU - Khdour, Omar

AU - Bandyopadhyay, Indrajit

AU - Visavadiya, Nishant P.

AU - Roy Chowdhury, Sandipan

AU - Hecht, Sidney

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85053903692&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053903692&partnerID=8YFLogxK

U2 - 10.1039/c8md00274f

DO - 10.1039/c8md00274f

M3 - Article

AN - SCOPUS:85053903692

VL - 9

SP - 1491

EP - 1501

JO - MedChemComm

JF - MedChemComm

SN - 2040-2503

IS - 9

ER -