Mitochondrial Dysfunction in Friedreich’s Ataxia

Raffaele Lodi; Doris J. Taylor; Anthony H.V. Schapira

doi:10.1159/000046891

Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia

Neurochemistry International ◽

10.1016/j.neuint.2017.08.002 ◽

2018 ◽

Vol 117 ◽

pp. 35-48 ◽

Cited By ~ 22

Author(s):

Shannon Chiang ◽

Danuta S. Kalinowski ◽

Patric J. Jansson ◽

Des R. Richardson ◽

Michael L.-H. Huang

Keyword(s):

Mitochondrial Dysfunction ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Degenerative Disease

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Mitochondrial dysfunction in neurons in Friedreich's ataxia

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2019.103419 ◽

2020 ◽

Vol 102 ◽

pp. 103419 ◽

Cited By ~ 4

Author(s):

Anna Stepanova ◽

Jordi Magrané

Keyword(s):

Mitochondrial Dysfunction ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia

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Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

Journal of the Neurological Sciences ◽

10.1016/j.jns.2005.03.012 ◽

2005 ◽

Vol 233 (1-2) ◽

pp. 145-162 ◽

Cited By ~ 262

Author(s):

Vittorio Calabrese ◽

Raffaele Lodi ◽

Caterina Tonon ◽

Velia D'Agata ◽

Maria Sapienza ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Mitochondrial Dysfunction ◽

Cellular Stress ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Cellular Stress Response

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Friedreich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction

Trends in Neurosciences ◽

10.1016/s0166-2236(96)20054-2 ◽

1996 ◽

Vol 19 (11) ◽

pp. 465-468 ◽

Cited By ~ 102

Author(s):

Toby J. Gibson ◽

Eugene V. Koonin ◽

Giovanna Musco ◽

Annalisa Pastore ◽

Peer Bork

Keyword(s):

Mitochondrial Dysfunction ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia

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Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Scientific Reports ◽

10.1038/s41598-020-72884-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Liwei Weng ◽

Laurent Laboureur ◽

Qingqing Wang ◽

Lili Guo ◽

Peining Xu ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mouse Models ◽

Human Subjects ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Mouse Heart ◽

Mitochondrial Enzymes ◽

Iron Sulfur Cluster ◽

Mouse Tissues ◽

Mature Mouse

Abstract Mature frataxin is essential for the assembly of iron–sulfur cluster proteins including a number of mitochondrial enzymes. Reduced levels of mature frataxin (81-20) in human subjects caused by the genetic disease Friedreich’s ataxia results in decreased mitochondrial function, neurodegeneration, and cardiomyopathy. Numerous studies of mitochondrial dysfunction have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, we have discovered that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

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P0222KIDNEY EFFECTS IN THE MOXIE TRIAL: A STUDY OF OMAVELOXOLONE IN PATIENTS WITH FRIEDRICH'S ATAXIA

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0222 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Philippe Zaoui ◽

Melanie Chin ◽

Martin Delatycki ◽

Paola Giunti ◽

Angie Goldsberry ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Mitochondrial Dysfunction ◽

Kidney Function ◽

Patient Population ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Average Increase ◽

Treatment Groups ◽

Organ Systems

Abstract Background and Aims Omaveloxolone, an Nrf2 activator, is an investigational drug that targets targets inflammation and mitochondrial dysfunction, metabolic, and bioenergetic pathways. Omaveloxolone is an analog of bardoxolone, methyl which has been shown to improve kidney function in multiple studies of chronic kidney diseases. The MOXIe Part 2 trial investigated omaveloxolone in patients with Friedreich’s ataxia (FA), a rare and serious hereditary disease caused by mitochondrial dysfunction that affects multiple organ systems resulting in ataxia, cardiomyopathy, and reduced lifespan. The study met its primary efficacy endpoint, and omaveloxolone improved neurological function, as assessed by the modified Friedreich’s ataxia rating scale (mFARS). We report the effect of omaveloxolone on kidney function in this patient population. Method The MOXIe trial (NCT02255435) was an international, multi-center, double-blind, placebo-controlled, randomized trial that enrolled 103 patients between 16 and 40 years of age with genetically confirmed FA. Patients were randomized 1:1 to receive either omaveloxolone 150 mg or placebo administered once daily for 48 weeks. The trial included 24 patients that were younger than 18 years of age. Baseline eGFR for the overall patient population receiving placebo or omaveloxolone was 109.2 ± 21.7 and 113.4 ± 14.7 mL/min/1.73 m2, respectively. Baseline eGFR for the pediatric population receiving placebo or omaveloxolone was 99.1 ± 33.7 and 106.3 ± 15.6 mL/min/1.73 m2, respectively. Serum creatinine was collected at baseline, Weeks 4, 12, 18, 24, 36 and 48 on-treatment and 4-weeks off-treatment at Week 52. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for patients ≥ 18 years of age. For patients <18 years of age, the Bedside Schwartz equation was used to calculate eGFR. Results In placebo patients, mean (SD) eGFR decreased by 4.4 ± 11.0 mL/min/1.73 m2 from baseline whereas patients receiving omaveloxolone had an average increase of +7.0 ± 10.7 mL/min/1.73 m2 from baseline after 48 weeks, resulting in a difference of 11.4 mL/min/1.73 m2 between treatment groups. At Week 52, mean eGFR was -4.2 ± 10.9 mL/min/1.73 m2 relative to baseline in placebo patients and remained +0.9 ± 10.8 mL/min/1.73 m2 above baseline in omaveloxolone patients after 4-weeks off-treatment. In pediatric patients randomized to placebo, at week 48 eGFR decreased by -11.3 ± 14.3 mL/min/1.73 m2 whereas patients receiving omaveloxolone had an average increase of +5.5 ± 14.5 mL/min/1.73 m2 from baseline, resulting in a difference of 16.8 mL/min/1.73 m2 between treatment groups. Conclusion Patients with FA randomized to placebo in the MOXIe trial had eGFR declines over 48 weeks that were similar to rates of decline observed in the most rapidly progressing forms of chronic kidney disease. The rapid kidney function decline in FA reflects the multi-system nature of the disease whereby mitochondrial dysfunction, and associated chronic inflammation, affects not only the central nervous system but also the heart and possibly the kidney. In contrast to placebo, treatment with omaveloxolone improved eGFR in patients with FA and the effects were sustained through one year of treatment. The durability of eGFR improvements are consistent with those observed with its analog, bardoxolone methyl, in clinical trials for various forms of CKD.

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