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Succinate : Accumulation stabilizes Hypoxia-Inducible Factor-1 (HIF-1), driving pro-inflammatory gene expression in macrophages (e.g., IL-1) ( -Ketoglutarate (-KG) : Acts as a cofactor for dioxygenases like TET enzymes and JMJD histone demethylases, influencing the epigenetic landscape and promoting anti-inflammatory phenotypes, such as regulatory T cell (Treg) differentiation ( Acetyl-CoA : Serves as the substrate for protein acetylation, including histone acetylation, which opens chromatin and facilitates the transcriptional programs necessary for immune cell activation ( 2.2.3 Reactive oxygen species signaling While excessive ROS causes oxidative damage, physiological levels of mitochondrial ROS (mtROS) are crucial second messengers that activate key signaling pathways like NF-B and NLRP3 inflammasome, amplifying inflammatory responses and enhancing antimicrobial activity in phagocytes ( 2.2.4 Regulation of apoptosis and innate immune signaling Mitochondria control the intrinsic apoptotic pathway by releasing Cytochrome C