Psychobiological Regulation of Cell-Free Mitochondrial DNA in Human Saliva

PROJECT SUMMARY Mitochondria are an emerging signaling organelle involved in stress regulation and mental health. Identifying mechanisms of mitochondrial signaling, including secreted molecules and their dynamic regulation, will provide the necessary tools to elucidate their role in stress pathophysiology and other disease conditions. We and others have recently established that mitochondria can release their own genome as cell-free mitochondrial DNA (cf- mtDNA), a potentially immunogenic molecule present in varying levels in human blood, particularly under conditions of psychological stress and psychopathology. Building on our recent discovery that cf-mtDNA is detectable in human saliva, we now propose foundational studies necessary to establish saliva cf-mtDNA as a useful marker for human research. Based on our preliminary studies, this 2-year R21 proposal aims to i) map the natural awakening response and diurnal variation of cf-mtDNA in healthy adult premenopausal women and in men; ii) define the association between cf-mtDNA and key steroid hormones with already well-defined diurnal rhythms, including cortisol; iii) leveraging already-collected saliva samples from a stress induction protocol, establish whether saliva cf-mtDNA is inducible by acute socioevaluative stress; and iv) whether saliva cf-mtDNA mirrors blood levels or whether cf-mtDNA is independently regulated in these two different biofluids. Together, these studies will establish potential sex differences in saliva cf-mtDNA dynamic across time scales, and provide the necessary basis to establish cf-mtDNA as a marker of mitochondrial stress in both mechanistic and epidemiological studies.