Dissecting the co-transcriptional processing of human mitochondrial mRNAs

• Applicant: Benedict Tan, Ph.D.
• Subject Area: Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555154282

Mitochondrial ATP synthesis via oxidative phosphorylation (OXPHOS) is vital for eukaryotic life. Its dysfunction leads to the development of various disease pathologies and is a characteristic feature of cellular ageing. Essential OXPHOS proteins are exclusively encoded by mitochondrial DNA, however despite its importance to human health, the dynamic regulation of mitochondrial gene expression is mechanistically poorly defined. This limits our understanding of the pathology of mitochondrial disease, and our ability to design effective therapies. Specifically, while several putative mitochondrial RNA-binding proteins have been identified, one particular and important aspect that has not been addressed so far is how the activity of such proteins are dynamically coordinated on nascent transcripts. Using human mitochondrial mRNA processing as a model system, we will employ biochemical reconstitution using purified recombinant proteins and nucleic acid substrates to investigate the functional coupling of mitochondrial transcription and RNA processing. Additionally, we will investigate whether co-transcriptional RNA processing is a mechanistic context that is perturbed by disease-associated protein mutations. Our results will give a detailed understanding how mitochondrial transcription and RNA processing are physically linked, and how the accuracy of RNA processing prevails over degradation and interference from antisense transcripts. We expect to develop innovative platforms using purified proteins for a context-specific manipulation of mitochondrial gene expression, thus yielding novel therapeutic targets.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Hauke Hillen