Sucralose promotes cardiac redox-metabolic remodeling through MRPL12-associated mitoribosomal stress

Mitochondrial redox imbalance and defective oxidative phosphorylation are central features of lipotoxic cardiac injury, but whether diet-related chemical exposures perturb cardiomyocyte mitochondrial gene-expression machinery remains unclear. Here, we investigated whether sucralose promotes cardiac redox-metabolic remodeling and lipid accumulation involving MRPL12-associated mitoribosomal impairment. Male C57BL/6J mice were exposed to sucralose in drinking water for 28 weeks; hiPSC-derived cardiomyocytes were used for mechanistic assays, and hiPSC-derived cardiomyocytes and H9c2 cardiomyoblast-like cells were used for lipid-accumulation assays under palmitic acid/oleic acid-induced lipid-loading conditions. Chronic sucralose exposure was associated with cardiac dysfunction, myocardial lipid accumulation, mitochondrial structural injury, ATP depletion, oxidative stress-associated signals, reduced glutathione redox buffering capacity, and reduced oxidative phosphorylation (OXPHOS) protein abundance. Quantitative cardiac proteomics identified mitochondrial ribosome- and oxidative phosphorylation-related changes, with MRPL12 emerging as a candidate mechanistic node. In cardiomyocytes, sucralose reduced MRPL12 abundance, altered the distribution of 39S/55S-enriched mitoribosomal fractions, suppressed residual nascent protein synthesis under cytosolic translation-suppressed conditions, reduced mitochondrially encoded OXPHOS proteins, impaired mitochondrial respiration, and aggravated lipid accumulation. Restoration of MRPL12 in cardiomyocytes or mouse hearts partially attenuated sucralose-associated redox-bioenergetic impairment, lipid deposition, and cardiac remodeling. Conversely, siRNA-mediated MRPL12 knockdown phenocopied key sucralose-associated abnormalities, including reduced abundance of mtDNA-encoded OXPHOS subunits, impaired respiration, increased mitochondrial superoxide-associated signal, and lipid accumulation. These findings support MRPL12-associated mitoribosomal impairment as a contributing mechanism linking sucralose exposure to mitochondrial redox-bioenergetic dysfunction and metabolic remodeling in the heart.