Defective biogenesis of human mitochondrial ribosomes causes sensorineural deafness

Abstract

Thirteen proteins of oxidative phosphorylation complexes encoded by mitochondrial DNA (mtDNA) were synthesized by own specific ribosomes (mitoribosomes). Mitoribosomes composed of nucleus-encoding proteins and mtDNA-encoding 12S and 16S ribosomal RNA. They are linked with sensorineural deafness and the targets of aminoglycosides. Mutations in nuclear genes encoding mitoribosome subunits cause syndromic deafness. The 12S rRNA 1555A > G and 1494C > T mutations have been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. These mutations create 1494C-G1555 or 1494U-A1555 base-pair at the A-site of 12S rRNA, make ribosomes more bacteria-like, thereby altering the binding for aminoglycosides and translation. These mutations conferred to mild mitochondrial dysfunctions, thereby requiring genetic and environmental factors to produce a deafness phenotype. The administration of aminoglycosides induces deafness in these subjects carrying the 12S rRNA mutations. Nuclear modifier including TRMU and mitochondrial modifier contributed to the tissue-specific phenotypic manifestation of 12S rRNA mutations. Especially, hair cell-like cells differentiated from patients-derived iPSCs harboring both m.1555A > G and TRMU c.28G > T mutations displayed greater defects in the morphology and functions than those in cells bearing only m.1555A > G mutation and these defects were restored by genetic correction of TRMU c.28G > T mutation. These provide new insights into pathophysiology of deafness, genetic counseling, prevention and therapeutic interventions for this disease.