Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is specifically activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for this activation remain elusive. A gene often associated with mtDNA mutations/deletions is Polg1 , which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe what is to our knowledge the first conditional muscle specific model of PolG mutation, and demonstrate a rapid development of mitochondrial dysfunction and cachexia in these animals from ∼5 months of age. Detailed molecular profiling of muscles demonstrated robust activation of the mtISR, likely mediated upstream by the HRI/DELE1 stress pathway. This was accompanied by striking alterations to the mitochondrial folate cycle and its metabolites, strongly implying imbalanced folate intermediates as a previously unrecognised pathology driving the mtISR in mitochondrial disease.