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.
Photodynamic therapy (PDT) shows very high potential for the clinical treatment of triple-negative breast cancer. However, the efficacy of PDT is significantly weakened by tumor hypoxia , the relatively high intracellular glutathione levels and the active proliferation of cancer cells. To address these issues, we developed a novel drug self-delivery nanorod (defined as AINRs) through the hydrophobic interaction among the mitochondrial complex III inhibitor (atovaquone, ATO), the photosensitizer (indocyanine green, ICG) and the dispersion stabilizer (distearoyl phosphoethanolamine-polyethylene glycol 2000, DSPE-PEG 2000). The AINRs showed a rod-like morphology with a mean diameter of 120.6 ± 5.4 nm , a zeta potential of −26.35 ± 1.63 mV and a significantly high drug loading rate of 93.48%. The results of in vitro cell experiments involving triple-negative breast cancer cell lines (4T1 cells and MDA-MB-231 cells) indicated that the AINRs could effectively block the oxidative phosphorylation of cancer cells through the inhibition of mitochondrial complex III, which results in the reduction of endogenous oxygen consumption and the decrease of the intracellular ATP level. The reduction of ATP content further inhibited the glutathione synthesis and arrested the cell cycle at the S-phase, which results in enhanced in vitro PDT efficacy of ICG. The results of in vivo antitumor activity in 4T1-bearing mice showed that the tumor growth inhibition rate of the AINRs with near-infrared laser irradiation (NIR) was greater than 90%, whereas the tumor growth inhibition rates of the AINRs without NIR, ICG with NIR and doxorubicin (3 mg/kg) were only 31.68%, 61.15% and 24.59%, respectively. In addition, the results of safety studies, including body weights, biochemical indicators and H&E staining images of the main organs demonstrated the security of the AINRs. In summary, this study showed that the oxidative phosphorylation inhibition of triple-negative breast cancer was a safe and effective method to enhance its PDT efficacy.
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