Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia

Perdomini, Morgane; Belbellaa, Brahim; Monassier, Laurent; Reutenauer, Laurence; Messaddeq, Nadia; Cartier, Nathalie; Crystal, Ronald G.; Aubourg, Patrick; Puccio, Hélène

doi:10.1038/nm.3510

Cited by 201 publications

(185 citation statements)

References 36 publications

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“…Similar to FRDA patients, the cardiac/skeletal muscle-specific FXN-KO mouse has impaired cardiac oxidative metabolism due to diminished activity of the ETC, which results in energy depletion and HF (16). Altogether, this mouse model develops HF that closely recapitulates the trajectory of disease in humans (19) and displays progressive increases in mitochondrial protein hyperacetylation, which, importantly, can be reversed with induction of Fxn expression via viral gene therapy (17,20). However, major questions remaining in the field include whether protein hyperacetylation contributes to the mitochondrial and metabolic abnormalities in HF and if targeting SIRT3 activation holds any therapeutic potential.…”

Section: Increasing Nadmentioning

confidence: 99%

“…Previous studies show progressive mitochondrial protein hyperacetylation in the FXN-KO heart by Western blotting (17,20). To identify these proteins, we performed isobaric tag-based quantitative proteomics, using well-established methods (21), on mitochondria collected from FXN-KO hearts at 5, 8, and 13 weeks of age (Supplemental Table 1; ProteomeXchange identifier PXD006754).…”

Section: Fxn-ko Cardiac Mitochondria Have Protein Hyperacetylation Rmentioning

confidence: 99%

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Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Martin¹,

Abraham

Hershberger³

et al. 2017

JCI Insight

114

110

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Section: Increasing Nadmentioning

confidence: 99%

Section: Fxn-ko Cardiac Mitochondria Have Protein Hyperacetylation Rmentioning

confidence: 99%

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Martin¹,

Abraham

Hershberger³

et al. 2017

JCI Insight

114

110

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“…70 In a conditional mouse model with complete frataxin deficiency in cardiac and skeletal muscle, the activities and levels of mitochondrial Fe-S proteins are much lower than in age-matched controls. 71 Consequently, mitochondrial iron levels are increased, with associated mitochondrial dysfunction and severe oxidative stress despite normal levels of iron in blood.…”

Section: Friedreich Ataxiamentioning

confidence: 99%

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Feingold¹,

Mahle²,

Auerbach³

et al. 2017

Circulation

223

195

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For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes. N euromuscular diseases (NMDs) encompass a broad spectrum of diagnoses with overlapping but distinct phenotypes. Common to many NMDs is cardiac involvement. Although the past 3 decades have seen marked advances in our understanding of many NMDs, significant gaps in knowledge remain on how best to approach cardiac care in these patients. For example, survival in Duchenne muscular dystrophy (DMD) has been extended through the use of glucocorticoid use and respiratory support, yet cardiac complications remain a significant cause of morbidity and mortality.1-3 To achieve further gains in care, we will need to improve our understanding of the pathophysiologies driving cardiac involvement in NMDs and advance treatments aimed at preventing the progression of heart failure (HF) and sudden death in NMDs. The recently published findings of an expert working group on cardiac involvement in DMD, which outlined key gaps in knowledge and made specific recommendations aimed at improving diagnosis and management, are a step toward this goal. 4 In this statement, we include a comprehensive overview of the major categories of NMDs with cardiac involvement. For each, a brief background of the gene defect(s), common clinical manifestations (particularly cardiac findings), and current therapies is summarized. Gaps in knowledge are highlighted, and where possible, clinical treatment suggestions are made by the expert writing group appointed by the American Heart Association to review the available literature. Selection of the writing group was performed in accordance with the American Heart Association's conflict-of-interest management policy. Participants volunteered to write sections relevant to their expertise and experience. CLINICAL STATEMENTS AND GUIDELINESconducted a general search of the literature, restricted to human subjects research published between 1980 and 2016. Drafts of each section were written and sent to the chair of the writing group for incorporation into a single document, which was then edited. The edited document was discussed electron...

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“…The length of the GAA expansion is proportional to the degree of frataxin deficiency in individuals with FRDA. Moreover, cardiomyopathy arises in patients with larger expansion, and it does not depend on the duration of the disease (30).…”

mentioning

confidence: 99%

Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury

Nanayakkara

Alasmari

Mouli

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 ␣ against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1␣ against I/R injury exerted via the mitochondrial protein frataxin, which regulates mitochondrial Fe-S cluster formation. Disruption of frataxin has been found to induce mitochondrial iron overload and subsequent ROS production. We observed that frataxin expression was elevated in mice hearts subjected to I/R injury, and this response was blunted in cardiomyocyte-specific HIF-1␣ knockout (KO) mice. Furthermore, these HIF-1␣ KO mice sustained extensive cardiac damage from I/R injury compared with control mice. Similarly, reduction of HIF-1␣ by RNA inhibition resulted in an attenuation of frataxin expression in response to hypoxia in H9C2 cardiomyocytes. Therefore, we postulated that HIF-1␣ transcriptionally regulates frataxin expression in response to hypoxia and offers a cardioprotective mechanism against ischemic injury. Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production, thus preserving mitochondrial membrane integrity and viability of cardiomyocytes. We postulate that frataxin may exert its beneficial effects by acting as an iron storage protein under hypoxia and subsequently facilitates the maintenance of mitochondrial membrane potential and promotes cell survival. The findings from our study revealed that HIF-1␣-frataxin signaling promotes a protective mechanism against hypoxic/ischemic stress.hypoxia-inducible factor-1␣; frataxin; iron-sulfur; mitochondria; ischemia-reperfusion NEWS & NOTEWORTHYThe present study provides evidence for a cardioprotective transcriptional regulatory mechanism by hypoxia-inducible factor-1␣ of the mitochondrial protein frataxin against ischemia-reperfusion injury. Frataxin regulates mitochondrial Fe-S cluster formation and protects against mitochondrial iron overload, the subsequent ROS production, and myocardial energy dysregulation.

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Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia

Cited by 201 publications

References 36 publications

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury

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