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: Jialing Yu, Jing Zheng, Xiaoxu Zhao, Junxia Liu, Zhuochao Mao, Yining Ling, Danni Chen, Chao Chen, Lanlan Hui, Limei Cui, Ye Chen, Pingping Jiang, Min-Xin Guan
• Journal: PloS one (PLoS One) Vol. 9 Issue 12 Pg. e114650 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25474306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gentamicins
• Mitochondrial Proteins
• RNA, Ribosomal
• RNA, ribosomal, 12S
• Reactive Oxygen Species
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (biosynthesis)
• Case-Control Studies
• Cell Line
• Energy Metabolism (drug effects)
• Female
• Gentamicins (pharmacology)
• Humans
• Membrane Potential, Mitochondrial
• Mitochondria (drug effects, physiology)
• Mitochondrial Proteins (metabolism)
• Mitophagy (drug effects, genetics)
• Organelle Shape
• Point Mutation
• RNA, Ribosomal (genetics)
• Reactive Oxygen Species (metabolism)
• Stress, Physiological