Research | Nils-Göran Larsson Group
Our research group is interested in fundamental questions related to mitochondrial biology. How is the number and the function of mitochondria regulated? What happens in a cell with dysfunctional mitochondria and how does mitochondrial dysfunction cause human disease?
Research interests
Mitochondria produce adenosine triphosphate (ATP), the energy currency of the cell, through the oxidative phosphorylation (OXPHOS) system. Mitochondria harbour their own genome, which encodes 13 of the OXPHOS components. The remaining components are encoded in the nucleus of the cell and imported into the mitochondria. We study the impact of mitochondrial dysfunction on disease and ageing using genetically modified mouse and fly models, molecular biology methods, and microscopy. Some examples of projects are described below.
Mitochondria and cancer
Cancer cells show a distinct metabolism compared to normal cells, since they are optimized for enhanced growth rather than performing specific functions in the body. Cancer cells are often more sensitive than healthy cells to mitochondrial dysfunction, and inhibition of mitochondrial function can therefore be a powerful method to treat cancer. We work on the development of drugs for cancer treatment by inhibiting mitochondrial transcription and translation.
Organization of the mitochondrial genome
Mammalian mitochondrial DNA (mtDNA) is organized into nucleoids. We have studied the ultrastructure of these nucleoids and found that they have an irregular ellipsoidal shape and typically contain a single copy of mtDNA. We have also suggested a mechanism for how mtDNA is packaged into nucleoids. The organisation of mtDNA into nucleoids is reviewed in Kukat and Larsson, Trends Cell Biol 2013.
Regulation of mitochondrial gene expression
To regulate the expression of the 13 proteins encoded by the mtDNA, several hundred proteins need to be imported into the mitochondria. We study the molecular machinery for replication, transcription and translation of mtDNA. Post-transcriptional mechanisms seem to play an important role. For a recent review on these topics see Hällberg and Larsson, Cell Metabolism 2014.
Mitochondria in ageing
We have created a knockin mouse with reduced proofreading activity during DNA replication. These mutator mice show increased levels of random point mutations and accumulate severe ageing phenotypes, showing that mtDNA mutations can cause a premature ageing phenotype. Different aspects of the role of mitochondria in mammalian ageing are discussed in Kauppila et al, Cell Metabolism 2017.
Mitochondria in neurodegenerative disorders
It has been suggested that mitochondrial dysfunction may be involved in the progressive neurodegenerative disorder Parkinson’s disease. To study this, we created several mouse models with neuron-specific inactivation of mtDNA genome maintenance, mitochondrial fusion or complex I deficiency. One of these models, the MitoPark mouse, recapitulates several features of Parkinson’s disease in humans and allows studies of disease progression.
Research environment
Our research group is part of the Division of Molecular Metabolism at the Department of Medical Biochemistry and Biophysics. We are located in Biomedicum, a newly built and modern facility for experimental research. We share equipment and have joint scientific meetings with Anna Wredenberg’s group and Joanna Rorbach’s group, who are also in our division.
Our research is highly integrated with clinical activities at the Center for Inherited Metabolic Diseases (CMMS) at Karolinska University Hospital. Several members of our division have shared employments between KI and CMMS and we have regular joint workshops. Close collaborators also include Claes Gustafsson’s group and Maria Falkenberg’s group at Gothenburg University, with whom we have yearly scientific gatherings known as MitoRetreats. In addition, we have a range of additional collaborators both nationally and internationally.
Our group is frequently involved in the organisation of international conferences and events related to mitochondrial biology and diseases.