International Journal of Clinical Case Reports, 2025, Vol.15, No.5, 239-247 http://medscipublisher.com/index.php/ijmms 242 function improves (Xi et al., 2024). SIRT3 turns on FOXO3a, and FOXO3a helps spread SIRT3’s protective effects (Wu et al., 2022; Tyagi and Pugazhenthi, 2023). 3 Research Advances in the Role of the SIRT3–FOXO3a Axis in Mitochondrial Homeostasis 3.1 Regulation of mitochondrial fusion/fission-related factors Mitochondria change shape all the time. They stay healthy by joining together (fusion) and splitting apart (fission). The SIRT3–FOXO3a axis helps control these changes. By deacetylating the protein OPA1, SIRT3 promotes mitochondrial fusion, enabling inner membranes to join and maintaining network stability (Murugasamy et al., 2022). In contrast, FOXO3a increases proteins like Drp1 and Fis1, which drive mitochondrial division When there’s oxidative stress, SIRT3 takes acetyl groups off FOXO3a. This lets FOXO3a enter the nucleus and turn on Drp1 and Fis1 genes. That helps the cell remove damaged mitochondria (Murugasamy et al., 2022). In diabetic muscle cells, this axis restores normal mitochondrial renewal (Xi et al., 2024). SIRT3 and FOXO3a jointly regulate mitochondrial fusion and fission. In septic cardiomyopathy, activating this axis may aid in removing damaged mitochondria and recovering normal function (Xian et al., 2025). 3.2 Role in mitochondrial mitophagy and biogenesis This axis mainly handles two tasks: clearing damaged mitochondria (mitophagy) and generating new ones (biogenesis) (Xi et al., 2024). During mitophagy, SIRT3 assists FOXO3a in activating genes such as Parkin. Parkin labels damaged mitochondria for removal (Tyagi and Pugazhenthi, 2023). When SIRT3 activates FOXO3a, Parkin expression increases, leading to more mitophagosomes that eliminate the damaged components (Xian et al., 2025). In diabetic mouse hearts, if SIRT3 is missing, FOXO3a doesn’t work well and mitophagy slows down. But restoring SIRT3 brings mitophagy back through the FOXO3a-Parkin pathway (Xi et al., 2024). This axis also works with PGC-1α, a protein that helps build new mitochondria. PGC-1α turns up the SIRT3 gene and supports energy production in mitochondria. In return, it relies on SIRT3 to help protect against oxidative stress (Wu et al., 2022). When SIRT3 is active, it helps both mitochondria grow and make more ATP. This works through the FOXO3a-PGC-1α pathway and is really helpful in septic cardiomyopathy (Wu et al., 2022). 3.3 Functions in mitochondrial ROS regulation and damage repair The SIRT3-FOXO3a axis helps lower ROS, clear it out, and fix the damage it causes (Wu et al., 2022; Tyagi and Pugazhenthi, 2023). FOXO3a helps make more antioxidant enzymes, such as MnSOD and Catalase. SIRT3 boosts FOXO3a’s activity, so these enzymes rise in the heart and other tissues. They clear away harmful molecules like superoxide and hydrogen peroxide (Wu et al., 2022). When SIRT3 activates FOXO3a, FOXO3a sticks to the promoters of MnSODand CAT, starting their transcription. These two enzymes then clean up ROS and help protect cells (Wu et al., 2022). SIRT3 also directly targets MnSOD, removing acetyl groups to enhance its ability to eliminate ROS (Tyagi and Pugazhenthi, 2023). In the absence of SIRT3, MnSOD remains acetylated, functions poorly, and allows ROS to accumulate, damaging the heart. Restoring SIRT3 helps lower ROS levels and improves heart performance (Trinh et al., 2024). FOXO3a also helps fix damaged DNA. It turns on repair genes like GADD45, which help with DNA repair (Chang et al., 2019). In septic cardiomyopathy, turning up this axis may boost the body’s antioxidant system and protect both mitochondria and DNA from ROS damage (Peng et al., 2024). Studies in patients back this up. Septic patients usually have lower SIRT3 and FOXO3a levels in their blood cells, and those with lower levels also show more oxidative stress. But survivors tend to have higher levels of this axis (Xin and Lu, 2020). 4 Involvement of the SIRT3–FOXO3a Axis in Oxidative Stress Signaling Regulation 4.1 Regulation of antioxidant enzyme expression The SIRT3-FOXO3a axis aids cells in coping with oxidative stress by regulating antioxidant enzyme production (Zhao and Liu, 2021; Wu et al., 2022). Through activating genes like Catalase and MnSOD2, FOXO3a promotes the removal of harmful ROS (Chang et al., 2019; Zhao and Liu, 2021). But FOXO3a needs SIRT3 to work well.
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