Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria

Figure 2

NRF2- and SIRT1-signaling pathways targeted by antioxidant compounds. Under normal homeostatic conditions, NRF2 transcriptional activity is inhibited by KEAP1 and PTEN. KEAP1 directly interacts with NRF2 and mediates its ubiquitination and subsequent proteasomal degradation. Furthermore, PTEN eliminates 3-phosphoinositides (PIP₃) required for AKT activation, thus leading to GSK3β activation and NRF2 phosphorylation. In vivo antioxidants act as electrophiles that modify and inhibit KEAP1 and PTEN. When KEAP1 is oxidized, its interaction with NRF2 is disrupted and NRF2 half-life increases. Electrophiles also inhibit the redox-sensitive phosphatase PTEN, allowing PIP₃ accumulation, AKT activation, and GSK3β inactivation. In these conditions, NRF2 is translocated to the nucleus where it binds to the electrophile response element (EpRE) and drives the expression of antioxidant defence genes. Additionally, antioxidant compounds modulate SIRT1 pathway favouring the antioxidant defence response and mitochondrial biogenesis by activation of FOXOa3 and PGC1α transcription factors, respectively.