Research
A defining feature of the eukaryotic cell is compartmentalised genomes with distinct modes of expression, transmission, and evolution. Mitochondria possess two dynamic membranes that envelop a multi-copy genome essential for aerobic energy metabolism. Metazoan mitochondrial DNA is one of the most constrained and simplified genomes found in cellular life and is completely dependent upon factors encoded within the nucleus for its maintenance and expression. How is mitochondrial gene expression monitored and regulated within the cell? Surprisingly, this very simple and basic question is very poorly understood in general let alone how it occurs under different cellular context such as mitosis, alterations to cell size or terminal differentiation to a post-mitotic state. My scientific goal is to understand the molecular mechanisms underpinning biological circuits needed for mitochondrial gene expression in human health and disease by identifying regulatory nodes that respond to disruptions that may vary temporally, spatially, and in magnitude.
Current projects
1. How often do errors in mitochondrial gene expression arise?
Our goal here is to reveal how mistakes in translation elongation are generated on mitochondrial ribosomes. Mistakes can arise from a number of causes, but the ones we are most interested in are those generated by faulty mRNA templates, heat shock, and antibiotics.
Since mitochondria are descended from an alpha-proteobacteria, many small molecules that inhibit bacterial protein synthesis also affect protein synthesis on mitochondrial ribosomes. Many off-target effects of antibiotic use are due to disruptions of mitochondrial gene expression. Our published research has elegantly demonstrated that these drugs can induce very different stresses within the organelle and on cell fitness. Thus, it is essential to understand the specific molecular defects that arise with these drugs.
Acute febrile infections are a pivotal moment in the natural history of patients with defects in mitochondrial gene expression, marking the progressive decline in patient health. Our current research has revealed how heat shock can modulate the translation of specific classes of mitochondrial DNA mutations.
The development of next generation sequencing approaches with single nucleotide resolution now allow us to investigate how often mistakes in mitochondrial mRNA templates arise.
The development of next generation sequencing approaches with single nucleotide resolution now allow us to investigate how often mistakes in mitochondrial mRNA templates arise.
2. How errors in mitochondrial translation elongation are recognised and resolved?
Severe stresses in translation elongation can be toxic! Therefore, mitochondria require responsive quality control pathways to recognise and resolve aberrations. Here we are investigating the molecular basis for two key steps in these pathways. Nucleolytic cleavage of mRNA on stalled ribosomes and the role of C12orf65 in releasing nascent chains from mitochondrial ribosomes.
3. How is mitochondrial gene expression coordinated with membrane biogenesis?
Our current research has identified a mechanism by which aberrations in mitochondrial nascent chain synthesis lead to acute remodelling of the mitochondrial inner membrane. The oxidative phosphorylation complexes are embedded in the cristae invaginations of the inner membrane, and our findings demonstrate that mitochondrial protein synthesis is a major determinant of this membrane ultrastructure. Therefore, there must be tight coordination between membrane biogenesis and mitochondrial protein synthesis but these mechanisms are poorly understood.
4. How is mitochondrial and nuclear gene expression coordinated?
Our research has revealed how selective disruptions to mitochondrial gene expression can have dramatically differential effects on cell fitness. Here, we use a number of model systems to tease apart the cytosolic pathways that monitor and respond to defects in mitochondrial gene expression. The ultimate goal being to identify the molecular basis by which signals are transmitted from the mitochondria to the nucleus and how these pathways are regulated across different cellular contexts such as mitosis, alterations to cell size or terminal differentiation to a post-mitotic state.