title: Aminoglycoside stress together with the 12S rRNA 1494C>T mutation leads to mitophagy.
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.
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Jialing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zhuochao
authors.initials: Z
authors.lastname: Mao
authors.affiliation: School of Agriculture and Biotechonlogy, Zhejiang University, Hangzhou, China.
authors.forename: Yining
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Danni
authors.initials: D
authors.lastname: Chen
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Hui
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Cui
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D016022:Case-Control Studies; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics*; D053140:Organelle Shape; D017354:Point Mutation; D012335:RNA, Ribosomal / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D005839:Gentamicins; D024101:Mitochondrial Proteins; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate