Abstract
Parkinson's Disease (PD) is a neurodegenerative disorder affecting more than 10 million people worldwide. Currently, PD has no cure and no early diagnostics methods exist. Mitochondrial dysfunction is presented in the early stages of PD, and it is considered an important pathophysiology component. We have previously developed mitochondria-targeted hydroxycinnamic acid derivatives, presenting antioxidant and iron-chelating properties, and preventing oxidative stress in several biological models of disease. We have also demonstrated that skin fibroblasts from male sporadic PD patients (sPD) presented cellular and mitochondrial alterations, including increased oxidative stress, hyperpolarized and elongated mitochondria and decreased respiration and ATP levels. We also showed that forcing mitochondrial oxidative phosphorylation (OXPHOS) in sPD fibroblasts uncovers metabolic defects that were otherwise hidden. In this work, we tested the hypothesis that a lead mitochondria-targeted hydroxycinnamic acid derivative would revert the phenotype found in skin fibroblasts from sPD patients.Our results demonstrated that treating human skin fibroblasts from sPD patients with non-toxic concentrations of AntiOxCIN4 restored mitochondrial membrane potential and mitochondrial fission, decreased autophagic flux, and enhanced cellular responses to stress by improving the cellular redox state and decreasing reactive oxygen species (ROS) levels. Besides, fibroblasts from sPD patients treated with AntiOxCIN4 showed increased maximal respiration and metabolic activity, converting sPD fibroblasts physiologically more similar to their sex- and age-matched healthy controls. The positive compound effect was reinforced using a supervised machine learning model, confirming that AntiOxCIN4 treatment converted treated fibroblasts from sPD patients closer to the phenotype of control fibroblasts.Our data points out a possible mechanism of AntiOxCIN4 action contributing to a deeper understanding of how the use of mitochondria-targeted antioxidants based on a polyphenol scaffold can be used as potential drug candidates for delaying PD progression, validating the use of fibroblasts from sPD patients with more active OXPHOS as platforms for mitochondria-based drug development.
Highlights
Parkinson’s Disease (PD) is a neurodegenerative disorder affecting more than 10 million people worldwide [1]
We recently demonstrated that metabolic and mito chondrial defects present in non-neuronal cells, such as fibroblasts from sporadic PD patients (sPD) patients, can be uncovered using a modified culture medium that stimulates mitochondrial adenosine triphosphate (ATP) production [43]
Using the same strategy in this work, we showed that metabolic and mitochondrial alterations observed in fibroblasts from sPD patients could be recovered by a new mitochondriotropic dietary antioxidant, proposing a potential mecha nism of action for the beneficial effects in mitochondrial function (Fig. 13)
Summary
Parkinson’s Disease (PD) is a neurodegenerative disorder affecting more than 10 million people worldwide [1]. PD is an incur able disease, with available drugs only alleviating symptoms. In more advanced stages of the disease, clinical treatment is no longer effective in controlling PD symptoms [2]. A small proportion of the PD cases results from genetic mutations, while around 85–90% of the cases are sporadic [5]. The etiology of sporadic PD is not fully understood, which results from the low number of experi mental models used, as well as the experimental difficulty in obtaining suitable human tissues to study PD pathogenesis [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
