The interplay of mtDNA maintenance proteins and mtRNA homeostasis, and how to study it

Speaker: Dr. Hans Spelbrink, Radboud University Medical Center, Nijmegen, the Netherlands

Talk:  The interplay of mtDNA maintenance proteins and mtRNA homeostasis, and how to study it

Time: 18.10.2024, 9:00 am

Venue: Intercollegiate Faculty of Biotechnology, Abrahama 58, hall 042B

Dr. Hans Spelbrink is a molecular cell biologist currently working at the Radboud University Medical Center, Nijmegen, the Netherlands. Since his PhD he has a long track record in mitochondrial research that has throughout the more than 25 years of research concentrated on mtDNA, its maintenance and expression. After moving to Finland in 1997, where he did a postdoc and subsequently started his own laboratory, he initiated the development of a polymerase gamma mutator model in human cells that has contributed also to the development of the mouse POLG1 mutator model (published in 2004), the analysis of which I took part in. In 2001, in a landmark paper published in Nature Genetics, he identified a novel mtDNA maintenance protein, which was the long sought-after mtDNA helicase, Twinkle, that was at the same time identified as the first mtDNA replication factor involved in human disease, namely autosomal dominant progressive external ophthalmoplegia. In two collaborative studies, Twinkle later also was shown to be involved in a recessive ataxia and in mtDNA depletion syndrome. Several subsequent studies (the most important ones published in 2007 & 2009) characterized Twinkle protein function using inducible cell cultures. These studies also addressed the mechanisms of mtDNA replication as did several other joint publications in more recent years. The characterization of Twinkle also provided the first clear demonstration that mtDNA in mammals (as shown in yeast many years earlier) was organized in discrete protein-DNA complexes within the mitochondrial network which contradicted the commonly held textbook view at that time that mammalian mtDNA was ‘naked’. In 2003 the nucleoid view was consolidated by demonstrating several other proteins such as TFAM and mtSSB to co-purify and co-localize with mtDNA in discrete structures. This research also suggested that nucleoids are amenable to biochemical isolation as he and others have shown in more recent publications. In 2010 he moved back to the Netherlands to join the Nijmegen Centre for Mitochondrial Disorders where he focused on establishing methods to more systematically identify nucleoid proteins using nucleoid targeted isolation methods in combination with mass-spectrometry. This research, in the last 5 years, has extended towards the more general identification and characterization of proteins involved with all aspects of mitochondrial gene expression. In his seminar, he will focus on the interplay between mtDNA maintenance and mitochondrial RNA homeostasis, focussing on cell biological and proteomic aspects of this interplay.