A mitochondria-targeted caffeic acid derivative reverts cellular and mitochondrial defects in human skin fibroblasts from male sporadic Parkinson's disease patients

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 AntiOxCIN 4 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 AntiOxCIN 4 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 AntiOxCIN 4 treatment converted treated fibroblasts from sPD patients closer to the phenotype of control fibroblasts. Our data points out a possible mechanism of AntiOxCIN 4 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.

Modulation of cellular redox environment as a novel therapeutic strategy for Parkinson's disease

“…As those fibroblasts from sPD patients have low ATP levels after treatment with AntiOxCIN 4 , AMPK‐α induces cell cycle arrest in S phase, in a p53‐dependent manner, to restore mitochondrial function, avoiding the perpetuation of cells with defective mitochondria (Figure 5). A general enhancement in mitochondrial fitness in fibroblasts from sPD patients is demonstrated by increased maximal respiration, decreased mitochondrial swelling, and increased cellular metabolic activity 145 . These and other findings highlight the successful development of new mitochondria‐directed antioxidants based on dietary scaffolds and demonstrate their application as first‐class candidates with therapeutic pontential for mitochondrial oxidative stress‐related diseases, such as PD.…”

“…A general enhancement in mitochondrial fitness in fibroblasts from sPD patients is demonstrated by increased maximal respiration, decreased mitochondrial swelling, and increased cellular metabolic activity. 145 These and other findings highlight the successful development of new mitochondria-directed antioxidants based on dietary scaffolds and demonstrate their application as first-class candidates with therapeutic pontential for mitochondrial oxidative stress-related diseases, such as PD.…”

“…140 More recently, we demonstrated using human skin fibroblasts from patients with sPD that AntiOxCIN 4 reverted metabolic and mitochondrial defects present in skin fibroblasts from sPD patients. 145 AntiOxCIN 4 works as mild pro-oxidant, which leads to the stimulation of the Nrf2 pathway (Figure 5), 144,145 having an important role in the cellular response to oxidants. Nrf2 stimulates the total SOD activity, consequently facilitating the conversion of O2 •into H 2 O 2 and inhibiting cell death induced by ROS.…”

Mitochondrial‐Targeting Vitamin B3 Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function

“…[40] Disruption of mitochondrial function was utilized to develop a PD model; [41] conversely, restoration of mitochondrial function could serve to ameliorate PD. [42] Rot, a highly toxic insecticide, has high lipophilicity and toxic effects on mitochondrial complex I, resulting in the production of oxidative species. In addition, Rot could specifically penetrate the blood-brain barrier, trigger an inflammatory response, and damage neuronal cells.…”

Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases

“…Specific drug delivery to mitochondria has been propelled by triphenylphosphonium (TPP), which is a lipophilic cation widely studied as a mitochondria-targeted agent [154,155]. Diverse TPP-linked antioxidants based on natural hydroxycinnamic derivatives have shown preferential mitochondrial localization and enhanced protection against oxidative damage and mitochondrial defects compared to free molecules both in cellular and animal models as well as in ex vivo assay with samples from NI&NDDs patients [156][157][158][159][160][161]. Likewise, TPP has been conjugated to different nanostructures for specific drug delivery and recovery of mitochondrial function in ND diseases.…”