Blood contains circulating cell‐free respiratory competent mitochondria

Abstract

Mitochondria are considered as the power‐generating units of the cell due to their key role in energy metabolism and cell signaling. However, mitochondrial components could be found in the extracellular space, as fragments or encapsulated in vesicles. In addition, this intact organelle has been recently reported to be released by platelets exclusively in specific conditions. Here, we demonstrate for the first time, that blood preparation with resting platelets, contains whole functional mitochondria in normal physiological state. Likewise, we show, that normal and tumor cultured cells are able to secrete their mitochondria. Using serial centrifugation or filtration followed by polymerase chain reaction‐based methods, and Whole Genome Sequencing, we detect extracellular full‐length mitochondrial DNA in particles over 0.22 µm holding specific mitochondrial membrane proteins. We identify these particles as intact cell‐free mitochondria using fluorescence‐activated cell sorting analysis, fluorescence microscopy, and transmission electron microscopy. Oxygen consumption analysis revealed that these mitochondria are respiratory competent. In view of previously described mitochondrial potential in intercellular transfer, this discovery could greatly widen the scope of cell‐cell communication biology. Further steps should be developed to investigate the potential role of mitochondria as a signaling organelle outside the cell and to determine whether these circulating units could be relevant for early detection and prognosis of various diseases.

A case for measuring both cellular and cell‐free mitochondrial DNA as a disease biomarker in human blood

“…50 Al Amir Dache et al, proposed that intact extracellular yet functional mitochondria can be detected in plasma, and showed ~10 7 mtDNA copies/ mL of plasma, which is ~100-1000 times greater than we observed in our samples with comparable nDNA levels. 51 The presence of intact mitochondria in the cf compartment of human peripheral blood could contribute to the mtDNA levels measured in ours and other studies and, if present in varying quantities could be responsible for some of the variation between our study and others. As with cellular mtDNA measurements, cf mtDNA copy number is usually determined using qPCR but cannot be normalized to a nuclear gene target.…”

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…Lastly, it should be mentioned that several cell types, and resting platelets, secrete respiratory competent mitochondria susceptible of autonomous extracellular signaling as well as of intercellular transfer, a finding of which the implications are still unclear but that could widely expand the scope of cell-cell communication biology [101]. To conclude, classifications mainly based on size do not fit the heterogeneity of the EV populations and their overlaps in cargo, biodistribution, and functions [102].…”

Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

“…We observed a strong negative association between MT DNA abundance and the number of In our PheWAS analysis, we found increased MT DNA abundance to be associated with increased risk of leukaemia, which is in agreement to prior findings which found higher MT DNA abundance to cause increased leukaemia risk 30,31 . Since an increased number of circulating lymphocytes is a hallmark of lymphoid leukaemia 32 A recent study presented evidence that cell-free and respiratory competent mitochondria are present in blood and may have a role in cell-cell communication 33 . Although the majority of DNA used for the genotyping experiments should be derived from nucleated cells, our current approach can, however, not distinguish between cellular and cell-free mitochondria.…”