A5084933832- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Cell death mechanisms and regulation
- CRISPR and Genetic Engineering
- RNA Interference and Gene Delivery
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- Endoplasmic Reticulum Stress and Disease
- RNA and protein synthesis mechanisms
- Adipose Tissue and Metabolism
- Autophagy in Disease and Therapy
- Lung Cancer Treatments and Mutations
- Photosynthetic Processes and Mechanisms
- Immune Cell Function and Interaction
- Epigenetics and DNA Methylation
- Cancer, Hypoxia, and Metabolism
- Genomics and Phylogenetic Studies
- Ubiquitin and proteasome pathways
- Muscle Physiology and Disorders
- Genomics, phytochemicals, and oxidative stress
- Genetics and Neurodevelopmental Disorders
- Vector-borne infectious diseases
- Exercise and Physiological Responses
- Machine Learning in Bioinformatics
- Mass Spectrometry Techniques and Applications
The University of Melbourne
2016-2024
Monash University
2020-2024
Australian Regenerative Medicine Institute
2021-2022
Walter and Eliza Hall Institute of Medical Research
2016-2021
Discovery Institute
2020-2021
La Trobe University
2013-2020
CSIRO Manufacturing
2020
Ruhr University Bochum
2010
Intrinsic apoptosis is critical to prevent tumor formation and engaged by many anti-cancer agents eliminate cells. BAX BAK, the two essential mediators of apoptosis, are thought be regulated through similar mechanisms act redundantly drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not function. Genetic deletion abrogated association BAK with mitochondrial complexes containing VDAC1,...
Abstract The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at lower end size distribution. Here, we show that mitochondrial proteome, particularly respiratory chain, enriched for proteins. Using a prediction and validation pipeline SEPs, report discovery 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics metabolic flux modeling, demonstrate BRAWNIN, 71...
Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for generating the majority of cellular ATP. Complex III (ubiquinol-cytochrome c oxidoreductase) third five OXPHOS complexes. assembly relies on coordinated expression mitochondrial and nuclear genomes, with 10 subunits encoded by DNA one (mtDNA). deficiency a debilitating often fatal disorder that can arise from mutations in complex subunit genes or three known factors. The molecular cause about half cases, however, unknown...
Mitochondrial complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly integration of distinct intermediate modules, mediated by numerous factors. The (MCIA) complex, containing factors NDUFAF1, ECSIT, ACAD9, TMEM126B, is required for building ND2-module. role MCIA involvement other proteins in this module unclear. Cell knockout studies reveal that while each component critical assembly, a hierarchy stability exists centered on ACAD9. We also...
Abstract The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. identification dependencies borne through common co-occurring mutations are sought more effectively -mutant cancer. Approximately 20% LUAD carry loss-of-function KEAP1 , negative regulator the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1 -deficient Kras G12D tumors arise from bronchiolar...
Abstract Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic intervention that can improve mitochondrial bioenergetics quality of life. By combining omics techniques with biochemical silico normalisation, we removed the bias arising from training-induced increase content to unearth intricate previously undemonstrated network differentially prioritised adaptations. We show changes hundreds transcripts, proteins,...
The vacuolating toxin VacA, released by Helicobacter pylori, is an important virulence factor in the pathogenesis of gastritis and gastroduodenal ulcers. VacA contains two subunits: p58 subunit mediates entry into target cells, p34 targeting to mitochondria essential for toxicity. In this study we found that dependent on a unique signal sequence 32 uncharged amino acid residues at N-terminus. Mitochondrial import mediated receptor Tom20 channel outer membrane TOM complex, leading insertion...
NDUFAB1 is the mitochondrial acyl carrier protein (ACP) essential for cell viability. Through its pantetheine-4'-phosphate post-translational modification, interacts with members of leucine-tyrosine-arginine motif (LYRM) family. Although several LYRM proteins have been described to participate in a variety defined processes, functions others remain either partially or entirely unknown. We profiled interaction network reveal associations 9 known as well more than 20 other involved respiratory...
Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist membrane insertion subunits, attachment co-factors, and stabilization assembly intermediates. The major fraction I, III IV are present together large molecular structures known as supercomplexes. Several have been proposed required for supercomplex assembly, including hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines extensive...
Cytochrome c oxidase (COX) assembly factor 7 (COA7) is a metazoan-specific factor, critical for the biogenesis of mitochondrial complex IV (cytochrome oxidase). Although mutations in COA7 have been linked to defects and neurological conditions such as peripheral neuropathy, ataxia, leukoencephalopathy, precise role plays not known. Here, we show that loss blocks after initial step where COX1 module built, progression from which requires incorporation copper addition COX2 COX3 modules. The...
Mitochondrial disease is a debilitating condition with diverse genetic etiology. Here, we report that TMEM126A, protein mutated in patients autosomal-recessive optic atrophy, participates directly the assembly of mitochondrial complex I. Using combination genome editing, interaction studies, and quantitative proteomics, find loss TMEM126A results an isolated I deficiency interacts number subunits factors. Pulse-labeling studies reveal associates newly synthesized DNA (mtDNA)-encoded ND4...
Preferential damage to fast, glycolytic myofibers is common in many muscle-wasting diseases, including Duchenne muscular dystrophy (DMD). Promoting an oxidative phenotype could protect muscles from and ameliorate the dystrophic pathology with therapeutic relevance, but developing efficacious strategies requires understanding currently unknown biological roles for dystrophin utrophin muscle adaptation plasticity. Combining whole transcriptome RNA sequencing mitochondrial proteomics...
Mitochondria are complex organelles containing 13 proteins encoded by mitochondrial DNA and over 1,000 on nuclear DNA. Many associated with the inner or outer membranes, either peripherally as integral membrane proteins, while others reside in of two soluble compartments, matrix intermembrane space. The biogenesis five complexes oxidative phosphorylation system exemplars this complexity. These large multi-subunit comprised more than 80 both peripheral associations require soluble, assembly...
Abstract Only half of individuals with suspected rare diseases receive a definitive genetic diagnosis following genomic testing. A allows access to appropriate patient care and reduces the number potentially unnecessary interventions related healthcare costs. Here, we demonstrate that an untargeted quantitative mass-spectrometry approach quantifying >6,000 proteins in primary fibroblasts representing >80% known mitochondrial disease genes can provide functional evidence for 83% cohort...
Inhibition of prosurvival BCL2 family members can induce autophagy, but the mechanism is controversial. We have provided genetic evidence that block autophagy by inhibiting BAX and BAK1, others proposed they instead inhibit BECN1. Here we confirm small molecule BH3 mimetics BAX- BAK1-independent MAP1LC3B/LC3B lipidation, this only occurred at concentrations far greater than required to apoptosis dissociate canonical domain-containing proteins bind more tightly Because high a less-active...
Sepsis remains to be a major contributor mortality in ICUs, and immune suppression caused by cell apoptosis determines the overall patient survival. However, diagnosis of sepsis‐induced lymphopenia problematic with no accurate prognostic techniques or biomarkers for death available. Developing reliable tools sepsis‐mediated is not only important identifying patients at increased risk but also monitor treatment progress currently trialed immunotherapy strategies. We have previously shown an...
CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting dysfunctional protein. It predominantly affects females and causes seizures first few months of life, ultimately severe intellectual disability. In absence targeted therapies, treatment currently only symptomatic. serine/threonine kinase that highly expressed brain, with critical role neuronal development. Evidence mitochondrial dysfunction...
Abstract Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist membrane insertion subunits, attachment co-factors, and stabilization assembly intermediates. The major fraction I, III IV are present together large molecular structures known as supercomplexes. A number have been proposed required for supercomplex assembly, including hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines...
SUMMARY Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible inexpensive therapeutic intervention improving mitochondrial bioenergetics quality of life. By combining a multi-omics approach with biochemical silico normalization, we removed the bias arising from training-induced increase human skeletal muscle content to unearth intricate previously undemonstrated network differentially prioritized adaptations. We show that changes hundreds...