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. 2026 Jun 10;17:1823729. doi: 10.3389/fphar.2026.1823729

FIGURE 4.

Four-panel scientific graphic explaining mitochondrial 12S rRNA mutation effects: Panel A contrasts normal and mutated 12S rRNA structures; Panel B illustrates increased aminoglycoside binding affinity in the mutant; Panel C models nuclear-mitochondrial gene interactions involved in rRNA modification; Panel D shows bar chart of m.1555A>G population prevalence by region, with highest rates in China and South Africa.

Genetic susceptibility to aminoglycoside ototoxicity: structural basis, nuclear modifiers, and population prevalence of the MT-RNR1 m.1555A>G variant. (A) Comparison of normal 12S rRNA (A1555, left) and mutated 12S rRNA (A1555G, right) at position 1,555 within helix 39. In the normal configuration, position 1,555 encodes adenine, producing a helix structure with limited hydrogen-bond donor capacity and low aminoglycoside binding affinity. The A→G substitution remodels helix 39 to structurally resemble the bacterial 16S rRNA decoding site (h44); guanine at position 1,555 introduces additional hydrogen-bond donors (N1 and N2 of guanine), enhancing aminoglycoside affinity (Hobbie et al., 2008; Guan et al., 2000; Guan, 2011). Hydrogen bonding changes are structurally inferred from comparative rRNA modelling and bacterial A-site homology; they have not been directly measured in human mitochondrial ribosomes. (B) Functional consequences of the structural change. Normal 12S rRNA (A1555) exhibits baseline aminoglycoside binding (∼1× affinity), preserving mitochondrial protein synthesis and function. Mutated 12S rRNA (A1555G) shows substantially increased aminoglycoside binding (∼5–10× affinity), resulting in impaired mitochondrial function even at therapeutic drug concentrations. Affinity values are schematic representations derived from differential ribosomal selectivity data rather than directly measured binding constants (Hobbie et al., 2008; Guan et al., 2000; Guan, 2011). (C) Proposed model of nuclear–mitochondrial interactions modulating penetrance of the m.1555A>G variant. Four nuclear modifier genes influence the phenotypic expression of MT-RNR1-associated ototoxicity: MTO1, GTPBP3, and TRMU participate in mitochondrial tRNA modification pathways; TFB1M methylates 12S rRNA at the mitochondrial ribosome (A10T variant of TFB1M reported to increase susceptibility approximately 2-fold) (Gao et al., 2017; Bykhovskaya et al., 2004). Aminoglycoside binding to the MT-RNR1-encoded 12S rRNA in the presence of these nuclear modifiers contributes to the variable and incomplete penetrance observed among carrier families. Carrier status does not predict clinical outcome; nuclear genetic background, environmental factors, and aminoglycoside exposure together influence penetrance. (D) General population carrier frequency of the m.1555A>G variant by population. European and US cohorts report consistent frequencies of approximately 0.19%–0.3%, while Chinese general population studies report a wider range of 0.14%–0.7%. The Taiwan estimate (0.1%) derives from a sensorineural hearing loss (SNHL) cohort rather than a general population screen and should be interpreted accordingly (Wu et al., 2007). The South African estimate (0.5%) is based on a small sample and should be interpreted with caution (Bardien et al., 2009). The European population estimate of approximately 1 in 520 is derived from the United Kingdom ALSPAC birth cohort (Bitner-Glindzicz et al., 2009). Among hearing-impaired populations, carrier frequency is substantially higher, particularly in East Asian cohorts, reflecting ascertainment bias. Other susceptibility variants are shown, including m.1494C>T (reported in East Asian populations), m.1095T>C (rarer, moderate susceptibility increase), and m.827A>G and m.961delT + C(n) (emerging evidence). Data sources: Population prevalence data from Bitner-Glindzicz et al. (2009), Vandebona et al. (2009), Gopel et al. (2014), Lu et al. (2010), Wu et al. (2007), Bardien et al. (2009), and Gaafar et al. (2024); prevalence table adapted from Usami & Nishio (GeneReviews) (Usami and Nishio, 1993). Hearing-impaired cohort frequencies from Guan et al. (2000) and Wu et al. (2007). Structural and binding concepts from Guan (2011), Guan et al. (2000), and Hobbie et al. (2008). Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; GTPBP3, GTP-binding protein 3; LBW, low birth weight; MT-RNR1, mitochondrially encoded 12S ribosomal RNA; MTO1, mitochondrial tRNA translation optimization 1; SNHL, sensorineural hearing loss; TFB1M, transcription factor B1, mitochondrial; TRMU, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase.