3 years ago

Tigecylcine induced inhibition of mitochondrial mtDNA translation may cause a lethal mitochondrial dysfunction in human

A 65-year old patient developed an unexplained and ultimately lethal metabolic acidosis under prolonged treatment with tigecycline. Tigecycline is known to have a selective inhibitory effect on eukaryotic mitochondrial translation. The underlying molecular mechanisms of the metabolic acidosis in this patient were explored. Methods OXPHOS analysis, blue native PAGE followed by in-gel activity staining in mitochondria, molecular analysis of mtDNA for genomic rearrangements and sequencing of the rRNA genes was performed on the proband’s skeletal muscle. Results OXPHOS analysis revealed a combined deficiency of the complexes I, III, IV and V, with a preserved function of complex II (encoded by nuclear DNA), thus demonstrating a defective mtDNA translation. There were no known underlying mitochondrial genetic defects. The patient had a (m.1391T>A) variant within the 12SrRNA gene in heteroplasmy (50-60%). Conclusion This patient developed an ultimately lethal mitochondrial toxicity under prolonged treatment with tigecycline, caused by a defective translation of the mtDNA. Tigecycline is known to suppress eukaryotic mitochondrial DNA translation, but until now this effect has been considered to be clinical insignificant. The observations in this patient suggest a clinical significant mitochondrial toxicity of tigecycline in this patient, and warrant further investigation.

Publisher URL: www.sciencedirect.com/science

DOI: S1198743X17304767

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