MITOCHONDRIAL GENE EXPRESSION: BASIC ASPECTS AND CONNECTION TO DISEASE

The human mitochondrial genome (mtDNA) is expressed and maintained by enzymatic machineries that are distinct from those used for these processes in the nucleus. These machineries are needed for correct oxidative phosphorylation system biogenesis.

During the last grant period, we have demonstrated that mutations in the mitochondrial transcription machinery can lead to human disease. Symptoms include global developmental delay, short stature, and speech/intellectual disability etc.

In the current research program we outline work to elucidate the molecular consequences of disease causing mutations in the transcription machinery.

We aim to elucidate how different point mutations in the same gene can cause radically different phenotypes in patients. Our work will be of importance for prenatal genetic counseling and the development of precision therapies.

Recently, we have also made a suprising discovery, which may change the way we think about mitochondrial transcription and its regulation. We have identified a new mitochondrial promoter.

The original promoters, HSP and LSP, were identified nearly 50-years ago and the discovery of a new, third promoter, termed LSP2, will force us to reinterpret many of the findings reported in the scientific literature over the past half century. In future work, we will elucidate the physiological importance of LSP2 and investigate its regulation.