Mitochondrial impairment of human muscle in Friedreich ataxia in vivo

Vorgerd, Matthias; Schöls, Lüdger; Hardt, Cornelia; Ristow, Michael; Epplen, Jörg T.; Zange, Jochen

doi:10.1016/s0960-8966(00)00108-5

Cited by 79 publications

(77 citation statements)

References 14 publications

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“…Previously, diminished mitochondrial respiration was observed in FXN-deficient cellular models, such as in yeast FXN *** *** homologues (⌬YFH1) and fibroblasts isolated from FRDA patients (6,32,57). In line with these findings, we also observed reduced basal mitochondrial respiration rates in our DOX-treated cardiomyoblasts (10 M for 24 h), as well as in our KD3 and FRDA fibroblasts.…”

Section: Fxn Overexpression Prevents Dox-mediated Reduction In Mitochsupporting

confidence: 91%

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Mouli

Nanayakkara

AlAlasmari

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

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Section: Fxn Overexpression Prevents Dox-mediated Reduction In Mitochsupporting

confidence: 91%

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Mouli

Nanayakkara

AlAlasmari

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Additionally, patients with FA (4) as well as heterozygous relatives of FA patients (5) exhibit an early-onset insulin resistance. Furthermore, we and others have demonstrated decreased ATP production in postexercise skeletal muscle in FA patients (6,7).…”

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confidence: 50%

“…The present finding that frataxin is an activator of OXPHOS in mammalian cells suggests that a deficiency of frataxin in tissues of patients with FA would lead to a defective OXPHOS. This view is supported by the recently published findings that the FA-phenotype in humans is associated with reduced ATP-levels in skeletal muscle during exercise (6,7). Additionally, a coenzyme Q derivate, idebenone, has been shown to ameliorate cardiac dysfunction in FA (51).…”

Section: Frataxin Activates Mitochondrial Respiration In Mammalian Cementioning

confidence: 73%

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Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

Ristow

Pfister²,

Yee³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

211

162

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Friedreich's ataxia (FA) is an autosomal recessive disease caused by decreased expression of the mitochondrial protein frataxin. The biological function of frataxin is unclear. The homologue of frataxin in yeast, YFH1, is required for cellular respiration and was suggested to regulate mitochondrial iron homeostasis. Patients suffering from FA exhibit decreased ATP production in skeletal muscle. We now demonstrate that overexpression of frataxin in mammalian cells causes a Ca 2؉ -induced up-regulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential (⌬ m) and results in an elevated cellular ATP content. Thus, frataxin appears to be a key activator of mitochondrial energy conversion and oxidative phosphorylation.

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“…For an underlying mechanism, a deficiency in peripheral ATP synthesis might be discussed, as described in patients with FA by us and others (29,30). Clearly, this study should be considered preliminary because of the small sample size and the fact that the study subjects were related.…”

Section: A B Gaa Expansions and Insulin Resistancementioning

confidence: 88%

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

et al. 2000

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Friedreich's ataxia (FA) is an autosomal recessive disease that has been attributed to a GAA triplet repeat expansion in the first intron of the X25/frataxin gene. Impaired glucose tolerance is present in up to 39% of FA patients, and clinically apparent diabetes is seen in ~18% of the affected individuals. Subjects carrying the X25/frataxin GAA repeat in a heterozygous state do not develop FA and, therefore, represent an ideal model to study the underlying metabolic defects that contribute to the diabetes associated with this disorder. In the present study, we have compared 11 first-degree relatives of FA patients (i.e., parents or heterozygous siblings of FA patients) with matched normal control subjects to study the parameters of glucose metabolism. An oral glucose tolerance test revealed diabetes in one of the heterozygous subjects who was excluded from further analyses. Using an octreotide-based quantification of insulin sensitivity, 8 of the remaining 10 study subjects showed pronounced insulin resistance, reflecting a significant difference from the control group (P = 0.001). In conclusion, a heterozygous expansion of the X25/frataxin GAA repeat in healthy individuals is associated with insulin resistance and might be considered a genetic co-factor in the pathogenesis of mitochondrial subtypes of diabetes. Diabetes 49:1604-1607, 2000 F riedreich's ataxia (FA) is phenotypically characterized by progressive ataxia and other neurological alterations in association with hypertrophic cardiomyopathy. The vast majority of FA patients carry a homozygous expansion of an intronic GAA tract of the X25/frataxin gene (1) leading to interference with the transcription of the frataxin gene (2) and subsequently decreasing expression of the frataxin protein (3). Frataxin is expressed in a wide variety of tissues, exhibits mitchondrial localization, and appears to be essential for embryonic development (4) in mice. Frataxin is most abundant in tissues with high metabolic activity, including skeletal muscle and brown fat (5). The characterization of the yeast frataxin homolog suggests a central role in oxidative phosphorylation (6). Furthermore, frataxin was proposed to regulate mitochondrial iron content (7,8) and to decrease oxidative damage to the cell (9,10). Frataxin is a mitochondrial protein that is significantly reduced in FA patients because of decreased transcription subsequent to expanded intronic GAA repeats on both copies of the X25/frataxin gene. Heterozygous carriers for this expansion are phenotypically normal but presumably exhibit a decreased expression of frataxin (2,11). In the present study, these heterozygous individuals were evaluated for alterations in glucose metabolism, specifically incidence of diabetes and insulin resistance.First, first-degree relatives of FA patients were genotyped, as described in RESEARCH DESIGN AND METHODS, to assure the presence of GAA expansions, especially in siblings of the patients. Eleven subjects from 4 different unrelated families were analyzed (8 parents and 3 sibli...

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Mitochondrial impairment of human muscle in Friedreich ataxia in vivo

Cited by 79 publications

References 14 publications

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

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