SS-31 Peptide Reverses the Mitochondrial Fragmentation Present in Fibroblasts From Patients With DCMA, a Mitochondrial Cardiomyopathy

Abstract

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. DCMA is a rare and 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. Skin 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. 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 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. Our results demonstrate the abnormal mitochondria in fibroblasts from patients with DCMA and suggest that SS-31 may represent a potential therapy for this devastating disease.

A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism

“…16 SS-31 has shown benefit in preclinical mitochondrial disorders and heart failure. 15,[17][18][19][20] We performed a randomized, double-blind, placebocontrolled crossover trial with an open-label extension to test the clinical efficacy and safety of daily administration of elamipretide in individuals with genetically confirmed Barth syndrome.…”

Drp1‐dependent peptide reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia

“…SS‐31 stabilizes the interaction between CL and ETC Complex II, thereby preventing cytochrome c release after exposure to oxidative stress. SS‐31 improves mitochondrial functioning and ameliorates oxidative damage in several disease models, including FRDA 27–31 . Certain biomarkers may be quantified to determine the effectiveness of drugs like SS‐31.…”

SS‐31 protect retinal pigment epithelial cells from H2O2‐induced cell injury by reducing apoptosis

“…21 SS-31 has several advantages, including the ability to inhibit reperfusion injury and mitochondrial swelling, protection against mitochondrial depolarization and substantial scavenging of ROS. [22][23][24] The antioxidative effect of SS-31 in the eye has been reported in several studies. Chen and colleagues have shown that SS-31 can protect human trabecular meshwork cell lines induced by oxidative stress by inhibiting caspase-3 activation.…”