Mitochondriotropic antioxidant based on caffeic acid AntiOxCIN(4) activates Nrf2-dependent antioxidant defenses and quality control mechanisms to antagonize oxidative stress-induced cell damage

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Amorim, R (Author) Other; Fernando Cagide (Author) FCUP; Tavares, LC (Author) Other; Simoes, RF (Author) Other; Soares, P (Author) Other; Benfeito, S (Author) Other; Baldeiras, I (Author) Other; Jones, JG (Author) Other; Fernanda Borges (Author) FCUP; Oliveira, PJ (Author) Other; Teixeira, J (Author) Other

Journal

Title: Free Radical Biology and Medicine

Vol. 179

Pages: 119-132

ISSN: 0891-5849

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 13 Citations

Other information

Authenticus ID: P-00W-3MJ

DOI: 10.1016/j.freeradbiomed.2021.12.304

Abstract (EN): Mitochondria are key organelles involved in cellular survival, differentiation, and death induction. In this regard, mitochondrial morphology and/or function alterations are involved in stress-induced adaptive pathways, priming mitochondria for mitophagy or apoptosis induction. We have previously shown that the mitochondriotropic antioxidant AntiOxCIN(4) (100 mu M; 48 h) presented significant cytoprotective effect without affecting the viability of human hepatoma-derived (HepG2) cells. Moreover, AntiOxCIN(4) (12.5 mu M; 72 h) caused a mild increase of reactive oxygen species (ROS) levels without toxicity to primary human skin fibroblasts (PHSF). As Nrf2 is a master regulator of the oxidative stress response inducing antioxidant-encoding gene expression, we hypothesized that AntiOxCIN(4) could increase the resistance of human hepatoma-derived HepG2 to oxidative stress by Nrf2-dependent mechanisms, in a process mediated by mitochondrial ROS (mtROS). Here we showed that after an initial decrease in oxygen consumption paralleled by a moderate increase in superoxide anion levels, AntiOxCIN(4) led to a time-dependent Nrf2 translocation to the nucleus. This was followed later by a 1.5-fold increase in basal respiration and a 1.2-fold increase in extracellular acidification. AntiOxCIN(4) treatment enhanced mitochondrial quality by triggering the clearance of defective organelles by autophagy and/or mitophagy, coupled with increased mitochondrial biogenesis. AntiOxCIN(4) also up-regulated the cellular antioxidant defense system. AntiOxCIN(4) seems to have the ability to maintain hepatocyte redox homeostasis, regulating the electrophilic/nucleophilic tone, and preserve cellular physiological functions. The obtained data open a new avenue to explore the effects of AntiOxCIN(4) in the context of preserving hepatic mitochondrial function in disorders, such as NASH/NAFLD and type II diabetes.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14