EXOSOMES IDENTIFIED A MITOCHONDRIAL PATHWAY OF EPIGENETIC PROGRAMMING IMPORTANT FOR TREATMENT RESPONSES IN DEPRESSION

Treatment resistant depression (TRD) is a leading cause of disability worldwide; there is a dearth of new mechanistic models for the development of personalized treatment models. Our group provide the first evidence that boosting mitochondrial metabolism of acetyl-L-carnitine(LAC) leads to a rapid and long-lasting antidepressant response in multiple rodent models by activating epigenetic processes of histone acetylation. Our translational work showed decreased levels of this pivotal mitochondrial metabolite LAC in phenotypes of TRD linked to childhood trauma. These LAC-deficient phenotypes were also characterized by a metabolic dysfunction known as insulin resistance. Unlike the role of systemic metabolism, the understanding of molecular mechanisms within key brain circuits has been limited to postmortem brain measures. Here, we used an innovative exosome technology to isolate neuronal exosomes from blood of patients with TRD and characterize key molecular markers of mitochondrial metabolism and the related epigenetic pathways at baseline and in treatment responses. Our ongoing analyses showed a link between a key mitochondrial marker assayed in neuronal exosomes and a treatment resistant course of illness. These phenotypes are also characterized by corresponding changes in the levels of activity of an epigenetic marker important for histone acetylation. These findings were specific to neuronal exosomes as no association was found in total(not neuronally-enriched) exosomes, suggesting a specificity for the brain. In all, these findings suggest that mitochondrial metabolism has important effects on epigenetic processes in patients with TRD and point to this model of mitochondrial-related epigenetic programming as a mechanistic pathway for the regulation of plasticity.