A5009876179- Mitochondrial Function and Pathology
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Adipose Tissue and Metabolism
- ATP Synthase and ATPases Research
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Metabolism and Genetic Disorders
- Autophagy in Disease and Therapy
- Metabolomics and Mass Spectrometry Studies
- Cancer-related molecular mechanisms research
- Muscle Physiology and Disorders
- Genetics and Neurodevelopmental Disorders
- Cancer, Hypoxia, and Metabolism
- Lipid Membrane Structure and Behavior
- Genomics and Phylogenetic Studies
- Genetic Neurodegenerative Diseases
Queen Elizabeth II Medical Centre
2018-2025
ARC Centre of Excellence in Synthetic Biology
2020-2025
The Kids Research Institute Australia
2023-2025
Princess Margaret Hospital for Children
2023-2025
The University of Western Australia
2018-2024
Perth Children's Hospital
2023-2024
Australian Research Council
2024
Harry Perkins Institute of Medical Research
2018-2023
The initiation of mitochondrial protein synthesis fine-tunes the assembly respiratory complexes and energy production.
Abstract The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address fundamental question we used CRISPR editing to knockout seven-membered phenylalanine gene family mice, both individually combinatorially. Using ATAC-Seq, RNA-seq, ribo-profiling proteomics observed distinct consequences single deletions. We show that tRNA-Phe-1-1 is required neuronal function its loss partially...
The regulation of mitochondrial RNA life cycles and their roles in ribosome biogenesis energy metabolism are not fully understood. We used CRISPR/Cas9 to generate heart- skeletal-muscle-specific knockout mice the pentatricopeptide repeat domain protein 1, PTCD1, show that its loss leads severe cardiomyopathy premature death. Our detailed transcriptome-wide functional analyses these enabled us identify molecular role PTCD1 as a 16S rRNA-binding essential for stability, pseudouridylation,...
Transcription of the human mitochondrial genome and correct processing two long polycistronic transcripts are crucial for oxidative phosphorylation. According to tRNA punctuation model, nucleolytic these large precursor occurs mainly through excision tRNAs that flank most rRNAs mRNAs. However, some mRNAs not punctuated by tRNAs, it remains largely unknown how non-canonical junctions resolved. The FASTK family proteins emerging as key players in RNA processing. Here, we have generated cell...
Breakdown of mitochondrial proteostasis activates quality control pathways including the unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond up-regulation chaperones proteases, we have a limited understanding how UPRmt remodels restores damaged proteomes. Here, developed functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect UPRmt's role in maintaining during stress. We find essential roles for both protecting...
During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses preserve cellular health. One such pathway integrated stress response (mtISR), which known be activated by DNA (mtDNA) damage. However, causal molecular signals responsible for activation of mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions Polg1, encodes Polymerase γ (PolG). Here, we describe an inducible, tissue specific model PolG...
Abstract Prostate cancer is the most commonly diagnosed malignancy and third leading cause of deaths. GWAS have identified variants associated with prostate susceptibility; however, mechanistic functional validation these mutations lacking. We used CRISPR‐Cas9 genome editing to introduce a missense variant in ELAC2 gene, which encodes dually localised nuclear mitochondrial RNA processing enzyme, into mouse Elac2 gene as well generate prostate‐specific knockout . These caused enlargement...
The influence of environmental insults on the onset and progression mitochondrial diseases is unknown. To evaluate effects infection disease we used a mouse model Leigh Syndrome, where missense mutation in Taco1 gene results loss translation activator cytochrome c oxidase subunit I (TACO1) protein. leads to an isolated complex IV deficiency that mimics pathology observed human patients with TACO1 mutations. We infected mutant wild-type mice murine cytomegalovirus show common viral...
The contribution of dysregulated mitochondrial gene expression and consequent imbalance in biogenesis is not well understood metabolic disorders such as insulin resistance obesity. ribosomal RNA maturation protein PTCD1 essential for synthesis its reduction causes adult-onset obesity liver steatosis. We used haploinsufficient Ptcd1 mice fed normal or high fat diets to understand how changes can lead dysfunction. show that Akt-stimulated lipid content upregulation effectively protected with...
ABSTRACT During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses preserve cellular health. One such pathway integrated stress response (mtISR), which specifically activated by DNA (mtDNA) damage. However, causal molecular signals responsible for this activation remain elusive. A gene often associated with mtDNA mutations/deletions Polg1 , encodes Polymerase γ (PolG). Here, we describe what our knowledge first conditional muscle...
ABSTRACT Breakdown of mitochondrial proteostasis activates quality control pathways including the unfolded protein response (UPR mt ) and PINK1/Parkin mitophagy. However, beyond upregulation chaperones proteases, we have a limited understanding how UPR remodels restores damaged mito-proteomes. Here, developed functional proteomics framework, termed MitoPQ ( Mito chondrial P roteostasis Q uantification), to dissect ’s role in maintaining during stress. We discover essential roles for both...