International Journal of Clinical Case Reports, 2025, Vol.15, No.5, 239-247 http://medscipublisher.com/index.php/ijmms 240 In this paper, we take a close look at how the SIRT3–FOXO3a axis keeps mitochondria balanced and deals with oxidative stress. We focus on how this pathway works in SCM and what it means for treatment. By doing this, we hope to better understand the disease and find new ideas for future drugs or gene-based therapies. 2 Molecular Mechanisms of the SIRT3-FOXO3a Axis 2.1 Deacetylation function and substrate specificity of SIRT3 SIRT3 is a key protein in mitochondria. It uses NAD⁺ to take away acetyl groups from other proteins. This helps keep mitochondrial proteins steady and supports normal cell metabolism (Wang et al., 2019; Zhang et al., 2020a). SIRT3 acts on many kinds of proteins. In fact, researchers have found that it can change hundreds of mitochondrial proteins. These include proteins from the electron transport chain, the TCA cycle, fat breakdown enzymes, and antioxidant systems (Figure 1) (Trinh et al., 2024). Figure 1 Key substrates of SIRT3 and its regulated mitochondrial functional pathways under cellular homeostasis (Adapted from Trinh et al., 2024) For instance, SIRT3 removes acetyl groups from LCAD and IDH2, aiding fat breakdown and boosting NADPH production (Trinh et al., 2024). It also targets MnSOD to help remove harmful ROS (Tyagi and Pugazhenthi, 2023). Without active SIRT3, these proteins remain acetylated and function poorly, a state linked to several diseases (Trinh et al., 2024; Zhang et al., 2024). 2.2 Transcriptional activity of FOXO3a and oxidative stress response pathways FOXO3a is part of the FOXO protein family. It helps cells deal with stress, especially from oxidation. It also takes part in cell death and cleanup processes, such as autophagy (Furukawa-Hibi et al., 2005; Fasano et al., 2019). When the PI3K-Akt pathway is active, Akt adds phosphate groups to FOXO3a at spots like T32 and S253. This makes FOXO3a bind to 14-3-3 proteins and stay in the cytoplasm. While it’s stuck there, it can’t enter the nucleus to turn on stress-fighting genes (Zhao and Liu, 2021).
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