Rearranged DNA in mitochondrial DNA maintenance disorders

Abstract

Mitochondrial genetics has been changing its focus during the last decade. Originally limited to describing effects of mutations of the mitochondrial DNA (mtDNA) research at present aims to understand circumstances of mutation generation and propagation in the context of mitochondrial genome maintenance. Key players of the mitochondrial DNA synthesis machinery have been thoroughly investigated by many research groups. However, little is known about the influence of other processes that are crucial for mtDNA maintenance. During my PhD study, I have been working on projects that seek to shed light on specific aspects of disturbances in mtDNA maintenance. (i) Investigating three families with an mtDNA maintenance disorder, we discovered a novel gene MGME1 that can process single stranded DNA molecules and flap structures, shows 5’-exonuclease activity, and probably plays a role in the process of replication and turn-over of replication intermediates, such as 7S DNA.<br /> (ii) Different factors that affect mitochondrial biogenesis in general might also influence mtDNA maintenance. Mitofusin 2 is one of these factors playing a crucial role in fusion of mitochondria, and thus in achieving an appropriate balance of mitochondrial dynamics. Pathogenic mutations in the MFN2 gene lead to mitochondrial fragmentation. We were able to show that alteration of mitochondrial dynamic leads to respiratory deficiency through a disturbed mtDNA replication.<br /> (iii) Our group developed techniques to investigate complex mixtures of large mtDNA deletions that are known to be involved in several human diseases, such as Parkinson’s and Alzheimer’s, as well as, in normal aging. We demonstrate that TLE with AHS, a rather common neurological disorder, is also associated with pathological changes in the mitochondrial genome. Analyzing detailed spectra of deletions we are able to investigate alterations of deletion patterns that might provide hints about different mechanisms leading to deletion generation.