Author: Caroline Trumpff1, Jeremy Michelson1, Claudia J Lagranha2, Veronica Taleon1, Kalpita R Karan1, Gabriel Sturm1, Daniel Lindqvist3, Johan Fernström4, Dirk Moser5, Brett A Kaufman2, Martin Picard6
1 Department of Psychiatry, Division of Behavioral Medicine, Columbia University Medical Center, New York, USA.
2 University of Pittsburgh, School of Medicine, Division of Cardiology, Center for Metabolism and Mitochondrial Medicine and Vascular Medicine Institute, Pittsburgh, PA, United States.
3 Faculty of Medicine, Department of Clinical Sciences, Psychiatry, Lund University, Lund, Sweden; Office of Psychiatry and Habilitation, Region Skåne, Sweden.
4 Faculty of Medicine, Department of Clinical Sciences, Psychiatry, Lund University, Lund, Sweden.
5 Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Bochum, Germany.
6 Department of Psychiatry, Division of Behavioral Medicine, Columbia University Medical Center, New York, USA; Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, USA; New York State Psychiatric Institute, NY, USA. Electronic address: email@example.com.
Date published: 2021 Jul 1
Other: Volume ID: 59 , Pages: 225-245 , Special Notes: doi: 10.1016/j.mito.2021.04.002. , Word Count: 212
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.
Keywords: Mitochondria; Non-inflammatory effects; Psychosocial stress; Standard protocol; cell-free DNA; mtDNA.
PMID: 33839318 PMCID: PMC8418815 DOI: 10.1016/j.mito.2021.04.002