Aminoglycoside Stress Together with the 12S rRNA 1494C&gt;T Mutation Leads to Mitophagy

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

doi:10.1371/journal.pone.0114650

Cited by 16 publications

(16 citation statements)

References 44 publications

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“…The total cellular levels of ROS generation in the vital cells derived from three mutant cell lines carrying the m.5655A → G mutation and three control cell lines lacking the mutation were measured with flow cytometry under normal conditions and under H 2 O 2 stimulation ( 32 , 40 , 43 ). Geometric mean intensity was recorded to measure the rate of ROS of each sample.…”

Section: Resultsmentioning

confidence: 99%

“…10A , the total cellular levels of ROS generation in the mutant cell lines carrying the m.5655A → G mutation varied from 103% to 115%, with an average of 110% ( P = 0.001) of the mean value measured in the control cell lines. Furthermore, the levels of mitochondrial ROS (mitoROS) among the cybrids were determined using a MitoSOX assay via flow cytometry ( 40 , 41 ). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Measurement of total cellular ROS generation was performed as detailed elsewhere ( 32 , 40 , 41 ). The level of ROS generation by mitochondria in living cells was analyzed using the mitochondrial superoxide indicator MitoSOX-Red (Invitrogen), as detailed previously ( 37 , 38 ).…”

Section: Methodsmentioning

confidence: 99%

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A Hypertension-Associated tRNA^Ala Mutation Alters tRNA Metabolism and Mitochondrial Function

Jiang

Wang

Xue

et al. 2016

Molecular and Cellular Biology

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In this report, we investigated the pathophysiology of a novel hypertension-associated mitochondrial tRNAAla 5655A → G (m.5655A → G) mutation. The destabilization of a highly conserved base pairing (A1-U72) at the aminoacyl acceptor stem by an m.5655A → G mutation altered the tRNAAla function. An in vitro processing analysis showed that the m.5655A → G mutation reduced the efficiency of tRNAAla precursor 5′ end cleavage catalyzed by RNase P. By using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA (mtDNA)-less (ρo) cells, we showed a 41% reduction in the steady-state level of tRNAAla in mutant cybrids. The mutation caused an improperly aminoacylated tRNAAla, as suggested by aberrantly aminoacylated tRNAAla and slower electrophoretic mobility of mutated tRNA. A failure in tRNAAla metabolism contributed to variable reductions in six mtDNA-encoded polypeptides in mutant cells, ranging from 21% to 37.5%, with an average of a 29.1% reduction, compared to levels of the controls. The impaired translation caused reduced activities of mitochondrial respiration chains. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These caused increases in the production of reactive oxygen species in the mutant cybrids. The data provide evidence for the association of the tRNAAla 5655A → G mutation with hypertension.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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A Hypertension-Associated tRNA^Ala Mutation Alters tRNA Metabolism and Mitochondrial Function

Jiang

Wang

Xue

et al. 2016

Molecular and Cellular Biology

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“…Measurement of ROS Production-ROS measurements were performed following the procedures detailed previously (51)(52).…”

Section: Methodsmentioning

confidence: 99%

Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation

Meng

Cang

Peng

et al. 2017

Journal of Biological Chemistry

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Nuclear modifier gene(s) was proposed to modulate the phenotypic expression of mitochondrial DNA mutation(s). Our previous investigations revealed that a nuclear modifier allele (A10S) in TRMU (methylaminomethyl-2-thiouridylate-methyltransferase) related to tRNA modification interacts with 12S rRNA 1555A→G mutation to cause deafness. The A10S mutation resided at a highly conserved residue of the N-terminal sequence. It was hypothesized that the A10S mutation altered the structure and function of TRMU, thereby causing mitochondrial dysfunction. Using molecular dynamics simulations, we showed that the A10S mutation introduced the Ser dynamic electrostatic interaction with the Lys residue of helix 4 within the catalytic domain of TRMU. The Western blotting analysis displayed the reduced levels of TRMU in mutant cells carrying the A10S mutation. The thermal shift assay revealed the value of mutant TRMU protein, lower than that of the wild-type counterpart. The A10S mutation caused marked decreases in 2-thiouridine modification of U34 of tRNA, tRNA and tRNA However, the A10S mutation mildly increased the aminoacylated efficiency of tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translation associated with the m.1555A→G mutation. The defective translation resulted in the reduced activities of mitochondrial respiration chains. The respiratory deficiency caused the reduction of mitochondrial ATP production and elevated the production of reactive oxidative species. As a result, mutated TRMU worsened mitochondrial dysfunctions associated with m.1555A→G mutation, exceeding the threshold for expressing a deafness phenotype. Our findings provided new insights into the pathophysiology of maternally inherited deafness that was manifested by interaction between mtDNA mutation and nuclear modifier gene.

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“…The copy number of mtDNA was determined by comparing the ratio of mtDNA to nDNA (β-actin) by real-time quantitative PCR as described previously [ 47 ]. The D-loop fragment was used as reference to determine the amount of mtDNA.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma

Qiao

Mao

et al. 2017

Oncotarget

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We investigated the role of mitochondrial genetic alterations in hepatocellular carcinoma by directly comparing the mitochondrial genomes of 86 matched pairs of HCC and non-tumor liver samples. Substitutions in 637 mtDNA sites were detected, comprising 89.80% transitions and 6.60% transversions. Forty-six somatic variants, including 15 novel mutations, were identified in 40.70% of tumor tissues. Of those, 21 were located in the non-coding region and 25 in the protein-coding region. Twenty-two somatic nonsynonymous changes were identified as putative pathogenic variants, including 4 truncating mutations produced by three frameshifts (MT-ATP6 8628 insC; MT-ND5 13475 T-del, and MT-CYB 14984 insA) and 1 nonsense mutation in MT-CO3 9253 G>A. Among the somatic variants, only m.13676 A>G (MT-ND5), found in only 1 tumor, was heteroplasmic. Both inherited and somatic variants were predominately located in the D-loop region and the MT-ND5 gene. Tumor/non-tumor paired analysis showed that 69% of HCC samples contained significantly reduced mtDNA, compared with 49.0% of non-tumor counterparts. In 81.40% of HCC samples, mitochondrial transcription factor A (TFAM) was enriched in tumor cells but not in adjacent non-tumor cells. Neither mtDNA depletion nor TFAM overexpression correlated with the degree of cell differentiation, though TFAM expression correlated with tumor size.

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Aminoglycoside Stress Together with the 12S rRNA 1494C>T Mutation Leads to Mitophagy

Cited by 16 publications

References 44 publications

A Hypertension-Associated tRNA^Ala Mutation Alters tRNA Metabolism and Mitochondrial Function

A Hypertension-Associated tRNA^Ala Mutation Alters tRNA Metabolism and Mitochondrial Function

Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation

Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma

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Aminoglycoside Stress Together with the 12S rRNA 1494C>T Mutation Leads to Mitophagy

Cited by 16 publications

References 44 publications

A Hypertension-Associated tRNAAla Mutation Alters tRNA Metabolism and Mitochondrial Function

A Hypertension-Associated tRNAAla Mutation Alters tRNA Metabolism and Mitochondrial Function

Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation

Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma

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A Hypertension-Associated tRNA^Ala Mutation Alters tRNA Metabolism and Mitochondrial Function

A Hypertension-Associated tRNA^Ala Mutation Alters tRNA Metabolism and Mitochondrial Function