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The Mitochondrial 28S ribosomal subunit (also known as the small mitoribosomal subunit or 30S-like subunit) is a ribonucleoprotein complex essential for the synthesis of the 13 proteins encoded by the mitochondrial genome (Greber & Ban, 2016). These proteins are critical components of the oxidative phosphorylation (OXPHOS) system, which generates the majority of cellular ATP (Hällberg & Larsson, 2014). Due to its evolutionary descent from bacterial ancestors, the 28S subunit shares structural homology with the bacterial 30S subunit, making it a frequent off-target for antibiotics such as aminoglycosides and tetracyclines (Kohanski et al., 2010). This cross-reactivity is a primary cause of drug-induced toxicities, including permanent hearing loss and kidney damage, particularly in individuals carrying specific mitochondrial DNA mutations like m.1555A>G (Guan, 2011). Beyond toxicity, the 28S subunit is an emerging therapeutic target in oncology; certain malignancies, including acute myeloid leukemia, demonstrate a heightened reliance on mitochondrial translation, suggesting that selective inhibition of the mitoribosome could serve as an effective anti-cancer strategy (Skrtic et al., 2011).
Inhibition of mitochondrial protein synthesis by binding to the 12S rRNA A-site, leading to translational misreading or termination (Kohanski et al., 2010).
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