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Dynamic behavior of cell-free mitochondrial DNA in human saliva

Mitochondria release their genome as cell-free mitochondrial DNA (cf-mtDNA) in multiple biofluids including in the blood, where it predicts mortality and is a marker of mental and physical stress. Here we report cf-mtDNA in human saliva, an accessible biofluid used to study dynamic neuroendocrine changes. To map the natural dynamics of salivary cf-mtDNA over time, we examine cf-mtDNA and steroid hormones in a small cohort of healthy adults, and perform an intensive repeated-measures analysis of two healthy men studied at 4 daily timepoints over 53-60 consecutive days (n=412-420 observations). Salivary cf-mtDNA exhibits a robust awakening response reaching up to two orders of magnitude 30-45 minutes after awakening, varies from day-to-day, and moderately correlates with the cortisol awakening response. Moreover, we find no evidence that salivary cf-mtDNA has pro-inflammatory effects. The dynamic behavior of salivary cf-mtDNA opens the door to non-invasive studies examining the relevance of mtDNA signaling on human health. Significance statement Mitochondria play a key role in the pathophysiology of many human diseases, but researchers currently lack tools to reliably assess mitochondrial function and signaling at scale. Circulating cell-free mitochondrial DNA (cf-mtDNA) in blood is a marker of mental and physical stress that predicts mortality, but it is not easily accessible in large studies. This study reports the existence of cf-mtDNA in human saliva, which exhibits a dynamic behavior, including a robust awakening response and within-person day-to-day variation. We describe a robust measurement approach and document weak associations of cf-mtDNA with other mitochondria-derived steroid hormones, suggesting new avenues to examine the neuroendocrine significance of mitochondrial signaling to human health.