Mitochondrial Peroxiredoxin 3 Is Rapidly Oxidized and Hyperoxidized by Fatty Acid Hydroperoxides

• Main Authors: Giuliana Cardozo (Author), Mauricio Mastrogiovanni (Author), Ari Zeida (Author), Nicolás Viera (Author), Rafael Radi (Author), Aníbal M. Reyes (Author), Madia Trujillo (Author)
• Format: Book
• Published: MDPI AG, 2023-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox12020408; 2076-3921
• Keywords: peroxiredoxin; mitochondria; fatty acid hydroperoxide; lipid peroxidation; antioxidant systems; kinetics; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 12, Iss 2, p 408 (2023)

Human peroxiredoxin 3 (<i>Hs</i>Prx3) is a thiol-based peroxidase responsible for the reduction of most hydrogen peroxide and peroxynitrite formed in mitochondria. Mitochondrial disfunction can lead to membrane lipoperoxidation, resulting in the formation of lipid-bound fatty acid hydroperoxides (_LFA-OOHs) which can be released to become free fatty acid hydroperoxides (_fFA-OOHs). Herein, we report that <i>Hs</i>Prx3 is oxidized and hyperoxidized by _fFA-OOHs including those derived from arachidonic acid and eicosapentaenoic acid peroxidation at position 15 with remarkably high rate constants of oxidation (>3.5 × 10⁷ M⁻¹s⁻¹) and hyperoxidation (~2 × 10⁷ M⁻¹s⁻¹). The endoperoxide-hydroperoxide PGG₂, an intermediate in prostanoid synthesis, oxidized <i>Hs</i>Prx3 with a similar rate constant, but was less effective in causing hyperoxidation. Biophysical methodologies suggest that <i>Hs</i>Prx3 can bind hydrophobic structures. Indeed, molecular dynamic simulations allowed the identification of a hydrophobic patch near the enzyme active site that can allocate the hydroperoxide group of _fFA-OOHs in close proximity to the thiolate in the peroxidatic cysteine. Simulations performed using available and herein reported kinetic data indicate that <i>Hs</i>Prx3 should be considered a main target for mitochondrial _fFA-OOHs. Finally, kinetic simulation analysis support that mitochondrial _fFA-OOHs formation fluxes in the range of nM/s are expected to contribute to <i>Hs</i>Prx3 hyperoxidation, a modification that has been detected in vivo under physiological and pathological conditions.