Anu Suomalainen Biomedicum-Helsinki, Molecular Neurology Research Program, University of Helsinki, Finland
Mitochondrial diseases manifest with an unprecedented clinical variability, affecting children and adults, and involving different organ systems. However, knowledge of the molecular mechanistic basis of such variability is lacking. To elucidate the tissue-specificity, we have created mouse models and stem cell-derived neural cultures for mtDNA replication defects and characterized tissue-specific metabolic consequences in the primary affected tissues and the whole organism. Using these disease models, we characterized an ”integrated mitochondrial stress response” (ISRmt), which has tissue-specific characteristics and involves transcriptional components, remodels one-carbon cycle and induces secretion of metabolic cytokines. This response is turned on in mtDNA expression disorders (mitotranslation, mtDNA deletions), but not in structural defects of the respiratory chain, indicating that the type of mitochondrial dysfunction determines the local stress responses. We present the orderly and sequential induction of ISRmt, with feed-back loops in mammalian tissues and cells. The metabolic component of ISRmt involves anabolic cytoplasmic biosynthesis reactions and activates mTORC1 in the skeletal muscle and the heart. Our results suggest that mitochondrial replisome and translation are part of a complex signaling system linking nutritional intake to energy metabolism, cellular biosynthetic reactions and organellar turnover. Furthermore, we propose that mitochondrial dysfunction modifies this signaling, which has consequences to disease progression. These pathways offer multiple strategies for intervention.