Tissue-specificity of integrated mitochondrial stress response in mitochondrial disease and aging Takayuki Mito1,2, Christopher Jackson1, Anastasiia Marmyleva1, Olesia Ignatenko1, Anu Suomalainen-Wartiovaara1,3,4* 1Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; 2Japan Society for the Promotion of Science, Tokyo 102-8472, Japan; 3Department of Neurology, Helsinki University Hospital, 00290 Helsinki, Finland; 4Neuroscience Center, University of Helsinki, 00790 Helsinki, Finland *Corresponding Author
Defects of mtDNA expression, such as mtDNA maintenance disorders, cause various stress responses such as expression of metabolic cytokine Fgf21, remodeling of one-carbon metabolism, and late-onset induction of mitochondrial heat-shock proteins. Recently, we showed that these processes are part of one integrated mitochondrial response (ISRmt) controlled by mTORC1 in muscles of mouse model for mitochondrial myopathy (Deletor mice). However, the systemic roles of ISRmt are not well understood, and also the basal changes of ISRmt through the whole life of healthy mice are unstudied. In order to address these points, we analyzed ISRmt in several tissues from different ages of Deletor mice and their controls by transcriptional and metabolomic analysis. We report that ISRmt is upregulated in the skeletal muscle and down-regulated in the liver from the early stage, much before the manifestations of disease signs. Also, we found that ISRmt is changed during aging of healthy mice, in a tissue and age specific way. These results suggest differential roles of ISRmt in different tissues, in different ages of mice, in health and disease.
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