Targeting taurine metabolism improves mitochondrial function in mt-tRNA mutation-associated mitochondrial disease

Background Mitochondrial diseases caused by mt-tRNA mutations disrupt oxidative phosphorylation and metabolic homeostasis, but effective treatment options remain scarce. Given the central role of nutrient metabolism in mitochondrial function, we investigated whether metabolite disturbances could reveal actionable therapeutic targets. Methods We conducted integrated transcriptomic and targeted metabolomic analyses in patients with mt-tRNA mutation-related mitochondrial disease, using skeletal muscle biopsies for transcriptome profiling and serum samples for metabolite assessment. The functional relevance of the identified metabolic alteration was tested in mutant cells following taurine supplementation. Results Transcriptomic analysis revealed coordinated upregulation of mitochondrial-encoded respiratory chain genes and downregulation of nuclear-encoded oxidative phosphorylation subunits, consistent with mito-nuclear transcriptional decoupling. Targeted serum metabolomics demonstrated a 26% reduction in taurine, accompanied by increased expression of genes involved in taurine biosynthesis and transport, suggesting a compensatory adaptation to systemic taurine deficiency. Importantly, taurine supplementation improved mitochondrial respiration, restored membrane potential, increased mtDNA content, and attenuated reactive oxygen species accumulation in mutant cells. Conclusions Our findings identify an association between altered taurine homeostasis and mt-tRNA mutation-associated mitochondrial dysfunction and provide in vitro evidence that taurine can modify selected mitochondrial parameters in an mt-tRNA mutation fibroblast model. These results provide a mechanistic rationale for future clinical studies targeting taurine metabolism in mitochondrial disorders.