Mitochondrial retrograde signalling responses in health and disease
Mitochondria are an ancestral endosymbiont with a small remnant of actively replicating DNA encoding essential genes for oxidative phosphorylation. Dependent on the cellular need and cell identity, this organelle drives diverse metabolic reactions including amino acid, nucleotide and lipid synthesis.
We investigate limiting metabolites for these reactions and the regulation of retrograde signalling pathways between the mitochondria and nucleus triggered by organelle dysfunction. These mechanisms have a direct role in the molecular pathogenesis of human disease and are associated with a broad spectrum of human pathology including neurodegenerative, cardiovascular and metabolic diseases, as well as cancer and ageing.
Understanding the molecular and metabolic events, governing these organelle-driven pathways and resulting elicited signalling responses induced by mitochondrial dysfunction, therefore is key in developing of potential therapeutic interventions.
Metabolic adaptations to mitochondrial dysfunction
Cancer cells often hijack mitochondrial anabolism for growth and ultimately cell fitness advantage. Intriguingly, defects in mitochondrial function elicit specific stress responses and cause metabolic changes similar to those observed in cancer cells.
This project aims to understand metabolic susceptibilities in various cell models of altered mitochondrial metabolism.
Cellular stress responses to mitochondrial dysfunction
Upon dysfunction, the mitochondria signal to the nucleus to alter and adapt nuclear gene expression, thereby eliciting specific transcriptional stress responses.
This projects aims to understand how these signals are transmitted to the nucleus and the subsequent programs initiated.
Mitoribosomal interactors triggered by dysfunction
The essential orchestration of nuclear and mitochondrial proteins synthesis to generate equimolar amounts of respiratory chain complexes encoded by two genomes suggest a higher order of regulation.
This projects aims to understand how mitochondrial translation is regulated upon mito-nuclear imbalance.