Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase

Purroy, Rosa; Medina-Carbonero, Marta; Ros, Joaquim; Tamarit, Jordi

doi:10.1016/j.redox.2020.101520

Cited by 20 publications

(15 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this work we have also analyzed the content of three PDH containing components. In primary cultures of frataxin-deficient neonatal rat ventricular cardiomyocytes (NRVMs) we had previously observed decreased PDHA1 content and disturbances in the redox state of DLAT-bound lipoic acid (Purroy et al, 2020). These previous results indicated a 40% loss of PDHA1 content, and no major changes in DLAT or DLDH content.…”

Section: Discussionmentioning

confidence: 86%

“…With this purpose, we decided to focus on several proteins or pathways that have been related with frataxin. In this regard, it has been described that frataxin deficiency causes loss of iron-sulfur containing proteins (Rotig et al, 1997), decreased function of the OXPHOS system (Lin et al, 2017), changes in the content of superoxide dismutases (Irazusta et al, 2006) , and decreased content of the pyruvate dehydrogenase component PDH A1 (Purroy et al, 2020) . Also, frataxin has been reported to interact with components of the iron-sulfur biosynthesis machinery (Patraa & Barondeaua, 2019), the OXPHOS system (Gonzalez-Cabo et al, 2005), and with the mitochondrial chaperone GRP75 (Shan et al, 2007) (Dong et al, 2019).…”

Section: Analysis Of Frataxin-related Proteins By Targeted Proteomicsmentioning

confidence: 99%

“…The 70 kDa band (which is more intense) corresponds to lipoic acid bound to DLAT (the E2 component from PDH), while three lipoic acid containing proteins migrate at 50 kDa. These are the E2 component from alpha-ketoglutarate dehydrogenase (Dihydrolipoyllysine succinyltransferase, DLST), the E2 component from the branched chain alpha-ketodehydrogenase complex, and the PDHbinding component X (a structural subunit from the PDH complex) (Purroy et al, 2020).…”

Section: Biosynthesis Of Lipoic Acid Is Not Compromised In Fxn I151f Micementioning

confidence: 99%

“…Frataxin deficiency has also been shown to impact on different pathways related to mitochondrial function. These include the OXPHOS system (Tamarit et al, 2016) (Lin et al, 2017), mitochondrial calcium efflux (Britti et al, 2021), mitochondrial permeability pore opening (Purroy et al, 2018), pyruvate dehydrogenase complex (Purroy et al, 2020), and endoplasmic reticulum-mitochondria contacts (Rodríguez et al, 2020), among others Generating mouse models to recreate FA has been challenging, as this disease is manifested when frataxin levels are below a pathological threshold. Therefore, animals must express some frataxin to be viable, but such expression may be lower than the pathological threshold required to trigger the disease.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia

Medina-Carbonero

Sanz-Alcázar

Britti

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease, caused by partial deficiency of frataxin, a mitochondrial protein. This deficiency is caused by the presence of a GAA triplet expansion in the first intron of the frataxin gene or, in some patients, by point mutations. Generating mouse models mimicking FA has been challenging, as this disease is manifested when frataxin levels are below a pathological threshold. In the present work, we have characterized a new mouse model of FA (FXNI151F) based on a pathological point mutation (I154F) present in some FA patients. These mice present very low frataxin levels in all tissues and display neurological deficits resembling those observed in FA patients. We have also observed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in the antioxidant defenses. Remarkably, these biochemical alterations precede the appearance of neurological symptoms and present a different profile in heart and brain or cerebellum. The FXNI151F mouse is an excellent tool for analyzing the consequences of frataxin deficiency in different tissues and for testing new therapies.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Analysis Of Frataxin-related Proteins By Targeted Proteomicsmentioning

confidence: 99%

Section: Biosynthesis Of Lipoic Acid Is Not Compromised In Fxn I151f Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia

Medina-Carbonero

Sanz-Alcázar

Britti

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ferroptosis execution usually requires both the presence of redox active iron and of decreased cellular antioxidant defenses, notably those involved in preventing lipid peroxidation such as GPX4 and reduced glutathione (GSH) 57 . In this regard, decreased GSH content and increased protein glutathionylation have been observed in fibroblasts from FA patients 58 and frataxin‐deficent cardiomyocytes 59 . Frataxin deficient cells also present decreased activity of NRF2, a transcription factor involved in adaptation to oxidative stress conditions 60 .…”

Section: The Role Of Iron In Friedreich Ataxiamentioning

confidence: 99%

Mitochondrial iron and calcium homeostasis in Friedreich ataxia

et al. 2021

Self Cite

View full text Add to dashboard Cite

Friedreich Ataxia is a neuro‐cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.

show abstract

Unusual Age‐Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia

Scarabino,

Veneziano,

Nethisinghe

et al. 2024

Movement Disorders

View full text Add to dashboard Cite

BackgroundFriedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene.ObjectiveThe aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age‐matched healthy subjects (n = 87).MethodsLTL was measured by real‐time polymerase chain reaction quantitative analysis (qPCR).ResultsThe results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)‐like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair.ConclusionsOverall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

show abstract

Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase

Cited by 20 publications

References 41 publications

Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia

Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia

Mitochondrial iron and calcium homeostasis in Friedreich ataxia

Unusual Age‐Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia

Contact Info

Product

Resources

About