Aminoglycoside stress together with the 12S rRNA 1494C>T mutation leads to mitophagy.

Jialing Yu,Yining Ling,Ye Chen,Min-Xin Guan,Zhuochao Mao,Xiaoxu Zhao,Jing Zheng,Lanlan Hui,Pingping Jiang,Limei Cui,Danni Chen,Junxia Liu,Chao Chen,Robert Lightowlers

doi:10.1371/journal.pone.0114650

Abstract

Aminoglycosides as modifying factors modulated the phenotypic manifestation of mitochondrial rRNA mutations and the incomplete penetrance of hearing loss. In this report, using cybrids harboring the m.1494C>T mutation, we showed that gentamycin aggravated mitochondrial dysfunction in a combination of the m.1494C>T mutation. The m.1494C>T mutation was responsible for the dramatic reduction in three mtDNA-encoded proteins of H-strand, with the average of 39% reduction, except of the MT-ND6 protein, accompanied with 21% reduction of ATP production and increase in mitochondrial reactive oxygen species, compared with those of control cybrids. After exposure to gentamycin, 35% reduction of mitochondrial ATP production was observed in mutant cybrids with a marked decrease of the mitochondrial membrane potential. More excessive cellular reactive oxygen species was detected with stimulus of gentamycin than those in mutant cells. Under gentamycin and m.1494C>T stress together, more dysfunctional mitochondria were forced to fuse and exhibited mitophagy via up-regulated LC3-B, as a compensatory protective response to try to optimize mitochondrial function, rather than undergo apoptosis. These findings may provide valuable information to further understand of mechanistic link between mitochondrial rRNA mutation, toxicity of AGs and hearing loss.

Highlights

Since the m.1555A.G and m.1494C.T mutations were first reported in families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) [1], [2], aminoglycosides (AGs) have been identified as one kind of modifying factors for hearing loss, modulating the phenotypic manifestation of m.1555A.G or m.1494C.T mutations
Our findings strongly suggest that compensatory protection will operate in the early stages of drug-induced hearing loss associated with m.1494C.T mutation to optimize mitochondrial function in a manner that differs from the results of long-term accumulation of drug toxicity [45]
It may provide valuable information to further understand of mechanistic link between mitochondrial rRNA mutation, AG ototoxicity and hearing loss

Summary

Introduction

Since the m.1555A.G and m.1494C.T mutations were first reported in families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) [1], [2], aminoglycosides (AGs) have been identified as one kind of modifying factors for hearing loss, modulating the phenotypic manifestation of m.1555A.G or m.1494C.T mutations. Since mitochondria are strongly implied as a primary targets in hearing loss induced by AGs [10], [11], more and more evidences have demonstrated that AGs decrease mitochondrial ATP synthesis [12], and induce excessive reactive oxygen species (ROS) production, which may trigger multiple forms of cell death via the JNK/MAPK or BCL2 pathway [13], [14]. It seems that AGs have wide-spectrum effects on mitochondrial function besides their effect on mitochondrial translation. We assume that compensatory protective activities may occur as initial effects of AG toxicity with genotoxicity together on mitochondrion

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