Regulatory Mechanisms of the Mitochondrial Control Region

Objetivo

Mitochondrial DNA (mtDNA) encodes 13 essential subunits of the oxidative phosphorylation (OXPHOS) system, the machinery that generates most of the cell’s ATP. The remaining ~1200 proteins required for mitochondrial function are encoded in the nucleus. Proper expression and maintenance of mtDNA are therefore indispensable: defects compromise OXPHOS and cause a wide spectrum of human disease, ranging from inherited mitochondrial disorders to age-related pathologies.

Over the past two decades, my laboratory has developed experimental systems, including the first in vitro reconstitutions of human mtDNA transcription (2002) and replication (2004), and integrated them with structural and cell biology approaches. This work helped define the transcription and replication machineries and identified key regulatory elements that cluster within the ~1.1 kb non-coding region (NCR). The NCR contains promoters for transcription and initiation/termination sites for replication, and is the central site coordinating genome expression and copy number control.

Yet the regulatory role of the NCR remains unexplored. This project moves beyond enzymatic mechanisms to define the regulatory principles of this control region, addressing long-standing questions that have remained unresolved. We will determine how transcription and replication are coordinated, how promoter firing is timed, and how these processes integrate to maintain genome stability. Our recent discoveries, including the molecular function of conserved non-coding 7S RNA and the identification of a human-specific promoter (LSP2), now make these key questions tractable.

This will be the first comprehensive definition of the NCR in mitochondrial genome regulation. By combining biochemistry with cellular approaches, we will resolve how mtDNA copy number is controlled and how genome stability is safeguarded, transforming understanding of mitochondrial genetics and its disruption in ageing and disease.