Louis Landau Chair in Child Health Research; NHMRC Leadership Fellow; Deputy Director, ARC Centre of Excellence for Synthetic Biology; Adjunct Research Professor, Monash University
BSc PhD
Aleksandra Filipovska is a Deputy Director of the ARC Centre of Excellence in Synthetic Biology, NHMRC Senior Research Fellow and Professor at The University of Western Australia. She received her PhD in 2002 from the University of Otago, New Zealand. From 2003-2005 she was a NZ Foundation for Research, Science and Technology Fellow at the MRC Mitochondrial Biology Unit in Cambridge, the United Kingdom.
In 2006 she relocated to Australia as a NHMRC Howard Florey Fellow and established her research group at the Perkins Institute of Medical Research at the University of Western Australia. She was an Australian Research Council Future Fellow until 2014 and since 2014 she has been a NHMRC Senior Research Fellow and Professor at UWA and the Harry Perkins Institute of Medical Research and established a Mitochondrial Disease Therapy group at Telethon Kids Institute in 2019. Her research interests are in the regulation of gene expression by RNA-binding proteins and the use of multi-omic technologies to elucidate their molecular functions in health and disease. Her research group uses genomic technologies and synthetic biology to design new models of cancer, metabolic and cardiovascular diseases, diagnose genetic diseases and develop treatments for these disorders.
- Projects
-
Publications
April 2024
Mutational rescue of the activity of high-fidelity Cas9 enzymes
Programmable DNA endonucleases derived from bacterial genetic defense systems, exemplified by CRISPR-Cas9, have made it significantly easier to perform genomic modifications in living cells. However, unprogrammed, off-target modifications can have serious consequences, as they often disrupt the function or regulation of non-targeted genes and compromise the safety of therapeutic gene editing applications.
Published research Mitochondrial Research Genomics MitochondriaJanuary 2024Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network
The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism disrupt mitochondrial structure and function.
Published research Mitochondrial Research MitochondriaOctober 2023Mitochondrial gene expression is required for platelet function and blood clotting
Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis.
Published research Mitochondrial Research Gene Expression MitochondriaSeptember 2023Temporal landscape of mitochondrial proteostasis governed by the UPRmt
Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes.
Published research Mitochondrial Research MitochondriaJuly 2023ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription
The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome requires separate enzymatic activities that can sterically compete, suggesting a life-long trade-off between these two processes.
Published research Mitochondrial Research Gene Expression MitochondriaMay 2023Digital RNase Footprinting of RNA-Protein Complexes and Ribosomes in Mitochondria
RNA-binding proteins and mitochondrial ribosomes have been found to be linchpins of mitochondrial gene expression in health and disease. The expanding repertoire of proteins that bind and regulate the mitochondrial transcriptome has necessitated the development of new tools and methods to examine their molecular functions.
Published research Mitochondrial Research Gene Expression MitochondriaMay 2023Molecular basis of translation termination at noncanonical stop codons in human mitochondria
The genetic code that specifies the identity of amino acids incorporated into proteins during protein synthesis is almost universally conserved. Mitochondrial genomes feature deviations from the standard genetic code, including the reassignment of two arginine codons to stop codons.
Published research Mitochondrial Research Genomics MitochondriaApril 2023Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer
Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking.
Published research Mitochondrial Research Gene Expression MitochondriaApril 2023Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation
The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially.
Published research Mitochondrial Research Genomics MitochondriaOctober 2022Frankenstein Cas9: engineering improved gene editing systems
The discovery of CRISPR-Cas9 and its widespread use has revolutionised and propelled research in biological sciences.
Published research Mitochondrial ResearchSeptember 2022ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing
Canonical RNA processing in mammalian mitochondria is defined by tRNAs acting as recognition sites for nucleases to release flanking transcripts. The relevant factors, their structures, and mechanism are well described, but not all mitochondrial transcripts are punctuated by tRNAs, and their mode of processing has remained unsolved.
Published research Mitochondrial ResearchApril 2022Organization and expression of the mammalian mitochondrial genome
The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation.
Published research Mitochondrial ResearchJuly 2021Preventative therapeutic approaches for hypertrophic cardiomyopathy
Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics.
Published research Mitochondrial ResearchJuly 2021Fidelity and coordination of mitochondrial protein synthesis in health and disease
The evolutionary acquisition of mitochondria has given rise to the diversity of eukaryotic life. Mitochondria have retained their ancestral α-proteobacterial traits through the maintenance of double membranes and their own circular genome. Their genome varies in size from very large in plants to the smallest in animals and their parasites. The mitochondrial genome encodes essential genes for protein synthesis and has to coordinate its expression with the nuclear genome from which it sources most of the proteins required for mitochondrial biogenesis and function.
Published research Mitochondrial ResearchJanuary 2021OmicsVolcano: software for intuitive visualization and interactive exploration of high-throughput biological data
Advances in omics technologies have generated exponentially larger volumes of biological data; however, their analyses and interpretation are limited to computationally proficient scientists. We created OmicsVolcano, an interactive open-source software tool to enable visualization and exploration of high-throughput biological data, while highlighting features of interest using a volcano plot interface. In contrast to existing tools, our software and user-interface design allow it to be used without requiring any programming skills to generate high-quality and presentation-ready images.
Published research Mitochondrial ResearchFebruary 2022In silico evolution of nucleic acid-binding proteins from a nonfunctional scaffold
Directed evolution emulates the process of natural selection to produce proteins with improved or altered functions. These approaches have proven to be very powerful but are technically challenging and particularly time and resource intensive. To bypass these limitations, we constructed a system to perform the entire process of directed evolution in silico.
Published research Mitochondrial ResearchFebruary 2022Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency
We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency.
Published research Mitochondrial ResearchNovember 2021The FASTK family proteins fine-tune mitochondrial RNA processing
Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs.
Published research Mitochondrial ResearchSeptember 2021A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance
Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the MRPP3 gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse Mrpp3 gene and show that the variant causes insulin resistance on a high-fat diet.
Published research Mitochondrial Research GenomicsJuly 2021The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication
We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis.
Published research Mitochondrial ResearchJune 2021Stepwise maturation of the peptidyl transferase region of human mitoribosomes
Mitochondrial ribosomes are specialized for the synthesis of membrane proteins responsible for oxidative phosphorylation. Mammalian mitoribosomes have diverged considerably from the ancestral bacterial ribosomes and feature dramatically reduced ribosomal RNAs. The structural basis of the mammalian mitochondrial ribosome assembly is currently not well understood. Here we present eight distinct assembly intermediates of the human large mitoribosomal subunit involving seven assembly factors.
Published research Mitochondrial ResearchJune 2021Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone or hyper-accurate mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner.
Published research Nutrition Mitochondrial ResearchJanuary 2021Investigating Mitochondrial Transcriptomes and RNA Processing Using Circular RNA Sequencing
Transcriptomic technologies have revolutionized the study of gene expression and RNA biology. Different RNA sequencing methods enable the analyses of diverse species of transcripts, including their abundance, processing, stability, and other specific features. Mitochondrial transcriptomics has benefited from these technologies that have revealed the surprising complexity of its RNAs. Here we describe a method based upon cyclization of mitochondrial RNAs and next generation sequencing to analyze the steady-state levels and sizes of mitochondrial RNAs, their degradation products, as well as their processing intermediates by capturing both 5' and 3' ends of transcripts.
Published research Mitochondrial Research -
Education and Qualifications
-
Awards/Honours
-
Active Collaborations