Abstract
Friedreich ataxia is a progressive neurodegenerative disease caused by the expansion of GAA trinucleotide repeats within the first intron of the FXN gene, which encodes frataxin. The pathophysiology of the disease is thought to be derived from the decrease of Fe-S cluster biogenesis due to frataxin deficiency. There is currently no effective treatment for the disease. In our study, we demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD+/NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia.
Highlights
No cure or effective treatment for FRDA has yet been reported, though a few clinical trials have made some limited progress[10]
We examined the effect of SS-31 treatment on lymphoblasts and fibroblasts derived from FRDA patients and found that SS-31 acts as an antioxidant to relieve the oxidative stress, and increases the protein level of FXN, which would be the fundamental resolution for FRDA patients
We optimised the condition for inducing the expression of FXN and found that the protein level of FXN increased in a dose dependent manner in both lymphoblasts and fibroblasts derived from patients (Fig. 1a and Fig. S1)
Summary
No cure or effective treatment for FRDA has yet been reported, though a few clinical trials have made some limited progress[10]. No available data for MitoQ in a clinical trial for FRDA is available Another therapeutic approach for FRDA is epigenetic modulation through heterochromatin acetylation by histone deacetylase inhibitor (HDACi) to increase the mRNA and protein levels of FXN16, 17. Researchers used synthetic DNA or RNA to block R-loop formation, thereby triggering FXN gene activation to levels similar to analogous wild-type cells[24]. This creates a new candidate strategy for FRDA treatment. We examined the effect of SS-31 treatment on lymphoblasts and fibroblasts derived from FRDA patients and found that SS-31 acts as an antioxidant to relieve the oxidative stress, and increases the protein level of FXN, which would be the fundamental resolution for FRDA patients. The aim of our study is to investigate whether the upregulated FXN expression induced by SS-31 treatment can improve mitochondrial function
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