A5053029687- Mitochondrial Function and Pathology
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- ATP Synthase and ATPases Research
- Cancer-related molecular mechanisms research
- Metabolism and Genetic Disorders
- RNA Research and Splicing
- Mesenchymal stem cell research
- Extracellular vesicles in disease
- Circular RNAs in diseases
- CRISPR and Genetic Engineering
- Genomics and Phylogenetic Studies
- Genetic Neurodegenerative Diseases
- Peptidase Inhibition and Analysis
- Tissue Engineering and Regenerative Medicine
- MicroRNA in disease regulation
- Renal and related cancers
- Genomics and Chromatin Dynamics
- Genetic Associations and Epidemiology
- Trace Elements in Health
- Ubiquitin and proteasome pathways
- Photosynthetic Processes and Mechanisms
Zhejiang University
2013-2024
Children's Hospital of Zhejiang University
2017-2024
Zhejiang International Studies University
2024
Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types cancer cells. Whether how affects cellular remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor modification, induces mitochondrial fission-to-fusion conversion breast cells via inhibiting ubiquitylation degradation fusion-promoting protein mitofusin 1 (MFN1) by SCFβ-TrCP E3 ligase blocking the translocation fusion-inhibiting DRP1. Importantly,...
Defective nucleotide modifications of mitochondrial tRNAs have been associated with several human diseases, but their pathophysiology remains poorly understood. In this report, we investigated the pathogenic molecular mechanism underlying a hypertension-associated 4435A→G mutation in tRNAMet. The m.4435A→G affected highly conserved adenosine at position 37, 3′ adjacent to tRNA's anticodon, which is important for fidelity codon recognition and stabilization. We hypothesized that introduced an...
Abstract Pseudouridine (Ψ) at position 55 in tRNAs plays an important role their structure and function. This modification is catalyzed by TruB/Pus4/Cbf5 family of pseudouridine synthases bacteria yeast. However, the mechanism TRUB underlying formation Ψ55 mammalian largely unknown. In this report, CMC/reverse transcription assays demonstrated presence human mitochondrial tRNAAsn, tRNAGln, tRNAGlu, tRNAPro, tRNAMet, tRNALeu(UUR) tRNASer(UCN). TRUB1 knockout (KO) cell lines generated...
Nuclear modifier gene(s) was proposed to modulate the phenotypic expression of mitochondrial DNA mutation(s). Our previous investigations revealed that a nuclear allele (A10S) in TRMU (methylaminomethyl-2-thiouridylate-methyltransferase) related tRNA modification interacts with 12S rRNA 1555A→G mutation cause deafness. The A10S resided at highly conserved residue N-terminal sequence. It hypothesized altered structure and function TRMU, thereby causing dysfunction. Using molecular dynamics...
Abstract Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting highly conserved adenosine at position 37, 3′ adjacent tRNA’s anticodon. Primer extension and methylation activity assays revealed that m.4295A>G introduced tRNA methyltransferase 5 (TRMT5)-catalyzed...
Mitochondria maintain a distinct pool of ribosomal machinery, including tRNAs and activating enzymes, such as mitochondrial tyrosyl-tRNA synthetase (YARS2). Mutations in YARS2, which typically lead to the impairment protein synthesis, have been linked an array human diseases optic neuropathy. However, lack YARS2 mutation animal model makes us difficult elucidate pathophysiology underlying deficiency. To explore this system, we generated knockout (KO) HeLa cells zebrafish using CRISPR/Cas9...
Abstract Mitochondrial DNA (mtDNA) mutations have been associated with Leber’s hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understood. In this study, we investigated the of a LHON susceptibility allele (m.3394T>C, p.30Y>H) in (MT)-ND1 gene. The incidence m.3394T>C mutation was 2.7% cohort 1741 probands LHON. Extremely low penetrances were observed 26 pedigrees carrying only mutation, while 21 families bearing m.3394T>C, together...
Leber's hereditary optic neuropathy (LHON) is a maternal inheritance of eye disease because the mitochondrial DNA (mtDNA) mutations. We previously discovered 3866T>C mutation within gene for ND1 subunit complex I as possibly amplifying progression patients bearing disease-causing 11778G>A ND4 I. However, whether and how exacerbates were unknown. In this report, we showed that four Chinese families both m.3866T>C m.11778G>A mutations exhibited higher penetrances LHON than 6 pedigrees carrying...
Mutations in the mitochondrial tRNAs have been reported to be important cause of hearing loss. However, only a few cases identified thus far and prevalence tRNA mutations hearing-impaired patients remain unclear. Here we performed mutational analysis 22 genes large cohort 887 Han Chinese subjects with loss by Sanger sequencing. The systemic evaluation putative pathogenic variants was further carried out frequency controls (<1%), phylogenetic analysis, structural...
Mitochondrial tRNA 3'-end metabolism is critical for the formation of functional tRNAs. Deficient mitochondrial linked to an array human diseases, including optic neuropathy, but their pathophysiology remains poorly understood. In this report, we investigated molecular mechanism underlying Leber's hereditary neuropathy (LHON)-associated tRNAAla 5587A>G mutation, which changes a highly conserved adenosine at position 73 (A73) guanine (G73) on acceptor stem. The m.5587A>G mutation was...
Abstract In this report, we investigated the molecular mechanism underlying a deafness-associated m.5783C &gt; T mutation that affects canonical C50-G63 base-pairing of TΨC stem tRNACys and immediately adjacent to 5′ end light-strand origin mitochondrial DNA (mtDNA) replication (OriL). Two dimensional agarose gel electrophoresis revealed marked decreases in intermediates including ascending arm Y-fork arcs spanning OriL mutant cybrids bearing mutation. mtDNA alterations were further...
Purpose: To investigate the mechanism underlying synergic interaction between Leber's hereditary optic neuropathy (LHON)-associated ND1 and mitochondrial tyrosyl-tRNA synthetase (YARS2) mutations. Methods: Molecular dynamics simulation differential scanning fluorimetry were used to evaluate structure stability of proteins. The impact 3635G>A YARS2 p.G191V mutations on oxidative phosphorylation machinery was evaluated using blue native gel electrophoresis enzymatic activities assays....
Inherited kidney diseases are the fifth most common cause of end-stage renal disease (ESRD). Mitochondrial dysfunction plays a vital role in progression inherited diseases, while mitochondrial-transfer RNA (mt-tRNA) variants and their pathogenic contributions to remain largely unclear. In this study, we identified mt-tRNAPhe 616T>C mutation 3 families documented that m.616T>C showed high threshold, with both heteroplasmy homoplasmy leading isolated chronic hyperuricemia without hematuria,...
Abstract In this report, we investigated the molecular mechanism underlying a deafness-associated m.7516delA mutation affecting 5′ end processing sites of mitochondrial tRNAAsp and tRNASer(UCN). An in vitro experiment demonstrated that caused aberrant tRNASer(UCN) precursors, catalyzed by RNase P. Using cytoplasmic hybrids (cybrids) derived from one hearing-impaired Chinese family bearing control, asymmetrical effects on tRNAs heavy (H)-strand light (L)-strand polycistronic transcripts....
The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within acceptor stem of mitochondrial tRNAHis. primary defect in this is an alteration tRNAHis aminoacylation. Here, we further investigate molecular mechanism 12201T>C and test whether overexpression human histidyl-tRNA synthetase gene (HARS2) cytoplasmic hybrid (cybrid) cells carrying reverses dysfunctions. Using dynamics simulations, demonstrate that perturbs structure function, supported by decreased melting...
Abstract Aim: To conduct the clinical, genetic, and molecular characterization of 494 Han Chinese subjects with tic disorders (TD). Methods: In present study, we performed mutational analysis 22 mitochondrial tRNA genes in a large cohort TD via Sanger sequencing. These variants were then assessed for their pathogenic potential phylogenetic, functional, structural analyses. Results: A total 73 gene (49 known 24 novel) on identified. Among these, 18 that absent or &lt;1% 485 control...
Defects in mitochondrial RNA metabolism have been linked to sensorineural deafness that often occurs as a consequence of damaged or deficient inner ear hair cells. In this report, we investigated the molecular mechanism underlying deafness-associated tRNAPhe 593T>C mutation changed highly conserved uracil cytosine at position 17 DHU-loop. The m.593T>C altered structure and function, including increased melting temperature, resistance S1 nuclease-mediated digestion conformational changes....
Alternative splicing (AS) is important in the regulation of gene expression and aberrant AS emerging as a major factor pathogenesis human conditions, including cancer. Triple-negative breast cancer (TNBC) most challenging subtype with strong invasion, high rate metastasis, poor prognosis. Here we report systematic profiling TNBC.The percent spliced (PSI) values for events 151 TNBC patients were obtained from The Cancer Genome Atlas (TCGA) SpliceSeq database. Univariate Cox stepwise...
Abstract A Chinese family with matrilineally inherited obesity was assessed and its clinical, genetic, molecular profiling conducted. Obesity observed in matrilineal relatives (3 out of 7) a single generation (of 3 alive generations) this family. On pedigree analysis sequencing their mitochondrial DNA (mtDNA), novel homoplasmic mutation the tRNACys gene (5802A&gt;G) identified these individuals. This correlated destabilized conserved base pair tRNA anticodon stem. Position 30 is known to...
Leber's hereditary optic neuropathy (LHON) is the maternal inheritance of eye disorder. LHON-linked mitochondrial DNA (mtDNA) mutations affect ND1, ND4 or ND6 genes encoding essential subunits complex I. However, role tRNA defects in pathogenesis LHON poorly understood. In this report, Sanger sequence analysis 22 identified 139 variants a cohort 811 Han Chinese probands and 485 control subjects. Among these, 32 (4 known 28 novel/putative) 71 may contribute to LHON, as these exhibited (1)...