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. 2022 Jun 19;15(6):764. doi: 10.3390/ph15060764

Figure 8.

Figure 8

Antioxidant therapies against FRDA. (a) Regulation of KEAP1–NRF2 complex, mTOR expression, lipid peroxidation, mitochondrial impairment and autophagy by antioxidant therapies results in the dissociation of KEAP1–NRF2 complex, restoration of mitochondrial respiration and biogenesis, and attenuation of lipid peroxidation. The dissociation of the KEAP1–NRF2 complex leads to the upregulation of downstream targets responsible for increased levels of antioxidant enzyme and gene, and attenuation of ROS production and pro-apoptotic activities. (b) Regulation of FXN expression and antioxidant enzymes by antioxidant therapies results in the promotion of FeS clusters biogenesis and restoration of mitochondrial function. Increased protein level of frataxin restores calcium regulation and attenuates neurofilament aggregate formation. The events ultimately lead to the attenuation of ROS production and pro-apoptotic activities. AMPK, AMP-activated protein kinase; ATG7, autophagy related 7; ATP, adenosine triphosphate; CAT, catalase; Cyt c, cytochrome c; DJ-1, protein deglycase; DRP1, dynamin-related protein 1; FXN, frataxin; GCL, γ-glutamyl cysteine ligase; GPX4, glutathione peroxidase 4; GRP75, glucose-regulated protein 75; GSH, glutathione; GSSG, oxidized glutathione; GSTM1, glutathione S-transferase mu 1; HO-1, heme oxygenase-1; KEAP1, Kelch-like ECH-associated protein 1; LC3, microtubule-associated protein 1A/1B-light chain 3; MFN1, mitofusin 1; MMP mitochondrial membrane potential; mTOR, mammalian target of rapamycin; NDUFS3, NADH: ubiquinone oxidoreductase core subunit s3; NFS1, cysteine desulfurase; NOQ1, NAD(P)H quinone oxidoreductase 1; NRF2, nuclear factor erythroid 2–related factor 2; NSF, N-ethylmaleimide-sensitive fusion protein; OGDH, 8-oxoglutarate dehydrogenase E1 component; PDH, pyruvate dehydrogenase; PGC-1α, peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1 alpha; PRDX2, peroxiredoxin 2; ROS, reactive oxygen species; SOD, superoxide dismutase; SRXN1, sulfiredoxin; TXNRD1, thioredoxin reductase 1.