Stress and circulating cell-free mitochondrial DNA: A systematic review of human studies, physiological considerations, and technical recommendations

Abstract

Cell-free mitochondrial DNA (cf-mtDNA) is a marker of inflammatory disease and a predictor of mortality, but little is known about cf-mtDNA in relation to psychobiology. A systematic review of the literature reveals that blood cf-mtDNA varies in response to common real-world stressors including psychopathology, acute psychological stress, and exercise. Moreover, cf-mtDNA is inducible within minutes and exhibits high intra-individual day-to-day variation, highlighting the dynamic regulation of cf-mtDNA levels. We discuss current knowledge on the mechanisms of cf-mtDNA release, its forms of transport (“cell-free” does not mean “membrane-free”), potential physiological functions, putative cellular and neuroendocrine triggers, and factors that may contribute to cf-mtDNA removal from the circulation. A review of in vitro , pre-clinical, and clinical studies shows conflicting results around the dogma that physiological forms of cf-mtDNA are pro-inflammatory, opening the possibility of other physiological functions, including the cell-to-cell transfer of whole mitochondria. Finally, to enhance the reproducibility and biological interpretation of human cf-mtDNA research, we propose guidelines for blood collection, cf-mtDNA isolation, quantification, and reporting standards, which can promote concerted advances by the community. Defining the mechanistic basis for cf-mtDNA signaling is an opportunity to elucidate the role of mitochondria in brain-body interactions and psychopathology.

Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports

“…Otherwise, cf-mtDNA may be removed via the liver, spleen, or kidney [62,75]. In septic patients with kidney injuries, cf-mtDNA levels are elevated in urine but not in plasma, supporting the idea that urine is a possible mechanism of cf-mtDNA elimination [76].…”

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

“…Interestingly, 5-HT 3 receptors are present in mitochondrial membranes, where they augment calcium ion uptake in hypoxia and increase the respiration control ratio in mice [ 342 ]. Furthermore, emerging studies revealed that blood in the normal physiological state contains whole functional cell-free mitochondria [ 343 , 344 ]. This observation may have profound implications for the field of inflammation and clinical applications [ 343 ], potentially involving signaling via 5-HT 3 receptors present in these mitochondrial membranes.…”

“…Furthermore, emerging studies revealed that blood in the normal physiological state contains whole functional cell-free mitochondria [ 343 , 344 ]. This observation may have profound implications for the field of inflammation and clinical applications [ 343 ], potentially involving signaling via 5-HT 3 receptors present in these mitochondrial membranes.…”

Plasma circulating cell-free mitochondrial DNA in depressive disorders

“…Increased ccf-mtDNA has been reported in various somatic disorders including sepsis, diabetes, and traumatic injury [ 2 – 5 ]. Recent studies show that also psychological stress may trigger ccf-mtDNA release [ 1 , 6 , 7 ], suggesting that this biomarker might be useful in certain psychiatric disorders.…”

“…While these findings suggest that depression and suicidality may be accompanied by increased amounts of cellular stress, other studies have reported unchanged [ 10 , 11 ], or decreased [ 12 ] ccf-mtDNA in mood disorders compared to healthy controls. As recently reviewed elsewhere [ 1 ], there are several factors relating to assay methodology and study design that might explain divergent findings across studies. Moreover, the use of psychotropic medications may influence mitochondrial function and cellular health [ 13 – 15 ].…”