Elamipretide Improves Mitochondrial Function in the Failing Human Heart

Chatfield, Kathryn C.; Sparagna, Genevieve C.; Chau, Sarah; Phillips, Elisabeth K.; Ambardekar, Amrut V.; Aftab, Muhammad; Mitchell, Max B.; Sucharov, Carmen C.; Miyamoto, Shelley D.; Stauffer, Brian L.

doi:10.1016/j.jacbts.2018.12.005

Cited by 75 publications

(74 citation statements)

References 51 publications

(56 reference statements)

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“…shows promise as a therapeutic for DCMA, paralleling results seen for other mitochondrial disorders and heart failure (21,22). Incubating cells with SS-31 for just 24 hours, and using a concentration similar to that previously documented to be safe and effective in vitro (38), the overall mitochondrial structure in patient fibroblasts improved significantly both qualitatively and quantitatively.…”

Section: Discussionsupporting

confidence: 52%

“…Despite the conflicting findings, the potential for abnormal mitochondrial structure and function in DCMA may represent a possible target for therapeutic intervention. The Szeto-Schiller peptide SS-31 (also known as elamipretide or Bendavia) interacts specifically with CL to affect membrane curvature and prevent peroxidative damage (17)(18)(19) and has shown pre-clinical promise as a treatment for mitochondrial disorders and heart failure (20)(21)(22). Our study aimed to characterize the structure and dysfunction of mitochondria found in primary dermal fibroblasts isolated from pediatric DCMA patients and to evaluate the effect of treatment with SS-31.…”

Section: Introductionmentioning

confidence: 99%

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SS-31 Reverses Mitochondrial Fragmentation in Fibroblasts from Patients with DCMA, a Mitochondrial Cardiomyopathy

Machiraju

Wang

Sabouny

et al. 2019

Preprint

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Objectives:We used patient dermal fibroblasts to characterize the mitochondrial abnormalities associated with the dilated cardiomyopathy with ataxia syndrome (DCMA) and to study the effect of the mitochondrially-targeted peptide SS-31 as a potential novel therapeutic.Background: DCMA is an understudied autosomal recessive disorder thought to be related to Barth syndrome but caused by mutations in DNAJC19, a protein of unknown function localized to the mitochondria. The clinical disease is characterized by 3-methylglutaconic aciduria, dilated cardiomyopathy, abnormal neurological development and other heterogeneous features. Until recently no effective therapies had been identified and affected patients frequently died in early childhood from intractable heart failure.Methods: Dermal fibroblasts from four pediatric patients with DCMA were used to establish parameters of mitochondrial dysfunction. Mitochondrial structure, reactive oxygen species (ROS) production, cardiolipin composition and gene expression were evaluated.Results: Immunocytochemistry with semi-automated quantification of mitochondrial structural metrics and transmission electron microscopy demonstrated mitochondria to be highly fragmented in DCMA fibroblasts compared to healthy control cells. Live-cell imaging demonstrated significantly increased ROS production in patient cells. These structural and functional abnormalities were reversed by treating DCMA fibroblasts with SS-31, a synthetic peptide that localizes to the inner mitochondrial membrane.Levels of cardiolipin were not significantly different between control and DCMA cells and were unaffected by SS-31 treatment. Conclusions:Our results demonstrate the abnormal mitochondrial structure and function in fibroblasts from patients with DCMA and suggest that SS-31 may represent a potential therapy for this devastating disease. Abbreviations List: CL = cardiolipin DCMA = dilated cardiomyopathy with ataxia syndrome DD = developmental delay FTT = failure to thrive LQT = prolonged QT interval LV = left ventricular LVEF = left ventricular ejection fraction PCA = principal components analysis ROS = reactive oxygen species TEM = transmission electron microscopy

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

SS-31 Reverses Mitochondrial Fragmentation in Fibroblasts from Patients with DCMA, a Mitochondrial Cardiomyopathy

Machiraju

Wang

Sabouny

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…14,15 Elamipretide is a mitochondria-targeting peptide, which reduces mitochondrial ROS and cytochrome C release, improving mitochondrial response to metabolic changes. 16 Due to its high affinity to cardiolipin, its ability to reduce oxidative stress and to prevent cytochrome peroxidase activity, elamipretide protects the architecture of mitochondria cristae. 9 By protecting mitochondria, elamipretide promotes an increased ATP production and decreased ROS production.…”

Section: Inhibition Of Apoptosis Of Retinal Ganglion Cellsmentioning

confidence: 99%

Treatment of Leber’s hereditary optic neuropathy: An overview of recent developments

Zuccarelli

Vella-Szijj

Serracino‐Inglott

et al. 2020

European Journal of Ophthalmology

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Leber’s hereditary optic neuropathy (LHON) is a rare, maternally-inherited optic neuropathy caused by mitochondrial DNA point mutations and which can cause blindness. Currently, Raxone (idebenone) is the only available medicinal product authorised to treat LHON within the European Union and LHON remains an unmet medical need. The aim of this article was to summarise interventional clinical trials published over the past 5 years (between 2014 and 2019) with the primary purpose of treating LHON. Therapeutic approaches discussed include modulating agents of the mitochondrial electron transport chain such as Raxone, cysteamine bitartrate and KH176, inhibitors of apoptosis such as elamipretide, gene therapy medicinal products such as GS010 and scAAV2P1ND4 and retinal tissue regeneration medicinal products such as bone marrow-derived stem cells.

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“…The mitochondria protective effect of SS31 after ischemia-AKI prevents prolonged inflammation and arrests CKD transition (Szeto et al, 2017). Elamipretide is on a phase 2a clinical trial in patients with atherosclerotic renal artery stenosis during stent revascularization, with promising results (NCT01755858; Saad et al, 2017) and was shown to improve mitochondria function in the human failing heart (Chatfield et al, 2019). The clinical effects of Elamipretide on kidney disease, however, require further investigations.…”

Section: Cardiolipin-targeting Peptidesmentioning

confidence: 99%

Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities

Lin

Duann

2020

Front. Physiol.

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To excrete body nitrogen waste and regulate electrolyte and fluid balance, the kidney has developed into an energy factory with only second to the heart in mitochondrial content in the body to meet the high-energy demand and regulate homeostasis. Energy supply from the renal mitochondria majorly depends on lipid metabolism, with programed enzyme systems in fatty acid β-oxidation and Krebs cycle. Renal mitochondria integrate several metabolic pathways, including AMPK/PGC-1α, PPARs, and CD36 signaling to maintain energy homeostasis for dynamic and static requirements. The pathobiology of several kidney disorders, including diabetic nephropathy, acute and chronic kidney injuries, has been primarily linked to impaired mitochondrial bioenergetics. Such homeostatic disruption in turn stimulates a pathological adaptation, with mitochondrial enzyme system reprograming possibly leading to dyslipidemia. However, this alteration, while rescuing oncotic pressure deficit secondary to albuminuria and dissipating edematous disorder, also imposes an ominous lipotoxic consequence. Reprograming of lipid metabolism in kidney injury is essential to preserve the integrity of kidney mitochondria, thereby preventing massive collateral damage including excessive autophagy and chronic inflammation. Here, we review dyslipidemia in kidney disorders and the most recent advances on targeting mitochondrial energy metabolism as a therapeutic strategy to restrict renal lipotoxicity, achieve salutary anti-edematous effects, and restore mitochondrial homeostasis.

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Elamipretide Improves Mitochondrial Function in the Failing Human Heart

Abstract: Visual Abstract

Cited by 75 publications

References 51 publications

SS-31 Reverses Mitochondrial Fragmentation in Fibroblasts from Patients with DCMA, a Mitochondrial Cardiomyopathy

SS-31 Reverses Mitochondrial Fragmentation in Fibroblasts from Patients with DCMA, a Mitochondrial Cardiomyopathy

Treatment of Leber’s hereditary optic neuropathy: An overview of recent developments

Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities

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