Nils-Göran Larsson Group
The mitochondrion is a key player in cellular function and dysfunctional mitochondria have been implicated in a number of disorders as well as in the process of normal ageing. Our knowledge of mitochondria is, however, still limited. How is the number and the funciton of mitochondra regulated? What happens in a cell with dysfunctional mitochondria?
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.
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.
|Eva Berglund||Research coordinator|
|Camilla Koolmeister||Research coordinator|
|Nils-Göran Larsson||Professor/senior physician|
|Henrik Spåhr||Senior research specialist|
|Susanne Virding||Biomedical scientist|
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- European Reserach Council
SLIRP stabilizes LRPPRC via an RRM-PPR protein interface.
Nucleic Acids Res. 2016 Aug;44(14):6868-82
POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA.
Sci Adv 2016 08;2(8):e1600963
Hierarchical RNA Processing Is Required for Mitochondrial Ribosome Assembly.
Cell Rep 2016 08;16(7):1874-90