Mitochondria‐targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants
Abstract
Friedreich Ataxia (FRDA), the most common inherited ataxia, arises from defective expression of the mitochondrial protein frataxin, which leads to increased mitochondrial oxidative damage. Therefore, antioxidants targeted to mitochondria should be particularly effective at slowing disease progression. To test this hypothesis, we compared the efficacy of mitochondria‐targeted and untargeted antioxidants derived from coenzyme Q 10 and from vitamin E at preventing cell death due to endogenous oxidative stress in cultured fibroblasts from FRDA patients in which glutathione synthesis was blocked. The mitochondria‐targeted antioxidant MitoQ was several hundredfold more potent than the untargeted analog idebenone. The mitochondria‐targeted antioxidant MitoVit E was 350‐fold more potent than the water soluble analog Trolox. This is the first demonstration that mitochondria‐targeted antioxidants prevent cell death that arises in response to endogenous oxidative damage. Targeted antioxidants may have therapeutic potential in FRDA and in other disorders involving mitochondrial oxidative damage.
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The EC50 for MitoQ in cultured cells is <0.5 nM, and the protective effect plateaus over several logs of concentration.
“In other studies, the EC50 for MitoQ in cultured cells was <0.5 nM, and the protective effect then plateaued over several logs of concentration (Jauslin et al., 2003).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Jauslin et al., 2003
The concentrations of MitoQ used here have no impact on mitochondrial functions such as ATP production, membrane potential, or ROS production in cells or mitochondria, but do prevent mitochondrial oxidative damage under conditions that lead to oxidative stress.
“There is extensive in vitro evidence that the concentrations of MitoQ used here have no impact on mitochondrial functions, such as ATP production, membrane potential, or ROS production in cells or mitochondria, but do prevent mitochondrial oxidative damage under conditions that lead to oxidative stress (Kelso et al., 2001; Jauslin et al., 2003; Saretzki et al., 2003; Asin-Cayuelaa et al., 2004).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Jauslin et al., 2003
MitoQ and MitoVitE have been shown to target mitochondrial dysfunction.
“Mitochondrially-targeted coenzyme Q (MitoQ) or mitochondrially-targeted vitamin E (MitoVitE) have been shown to target mitochondrial dysfunction282,283.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [283]
Mitochondrial-targeted antioxidants protected Friedreich ataxia fibroblasts, in which glutathione synthesis was blocked, from oxidative stress.
“Mitochondrial-targeted antioxidants protected Friedreich ataxia fibroblasts, in which glutathione synthesis was blocked, from oxidative stress (148)”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [148]
In glioma cells, astrocytes, and macrophages, Fpn associates with ceruloplasmin (Cp).
“In glioma cells, astrocytes, and macrophages, Fpn associates with ceruloplasmin (Cp) (123, 148).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [148]
Inability to export iron may explain tissue iron accumulation.
“Inability to export iron may explain tissue iron accumulation.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [148]
Adult Cp-knockout mice exhibit accumulation of iron in the cerebellum and brainstem that correlates with development of deficits in coordination of movement.
“Adult Cp-knockout mice exhibited accumulation of iron in the cerebellum and brainstem that correlated with the development of deficits in coordination of movement (148).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [148]
GPI-anchored Cp is required for export of iron from astrocytes.
“GPI-anchored Cp was required for export of iron from astrocytes (148) (Table 4).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [148]
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“The results with mitochondria-targeted ubiquinone (MitoQ) or mitochondria-targeted carboxy-proxyl (Mito-CP) so far have shown promising results in preventing mitochondrial abnormalities and nitroxidative tissue injury in various disease models including Friedreich Ataxia fibroblasts [224], diabetic nephropathy [225],…”
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- Authors
- Jauslin, M. L., Meier, T., Smith, R. A. J., & Murphy, P. M.
- Affiliations
- Geotech Co., Ltd. (Japan) (JP)
- University of Otago (NZ)
- MRC-Dunn Human Nutrition Unit Cambridge CB2 2XY United Kingdom
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2003-08-15
- Volume
- 17
- Issue
- 13
- Pages
- 1-10
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2154919554
- Cited by
- 358
- References
- 21
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 8 · 2023: 14 · 2022: 11 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 13 · 2017: 9 · 2016: 11 · 2015: 14 · 2014: 17 · 2013: 19 · 2012: 21
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission (QLRT-CT-1999-00584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- Friedreich's ataxia, mitochondria-targeted antioxidants, oxidative stress, frataxin, mitochondrial oxidative damage, MitoQ, idebenone, Trolox, vitamin E, coenzyme Q10, glutathione deficiency, fibroblasts, cell death, mitochondrial disease therapy
- MeSH terms
- Antioxidants, Fibroblasts, Friedreich Ataxia, Humans, Mitochondria, Models, Biological, Organophosphorus Compounds, Ubiquinone, Vitamin E, Benzoquinones, Drug Delivery Systems, Cell Death, Oxidative Stress
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