Alain R. Thierry
Inserm Research Director
Unit 1194 Montpellier Cancer Research Institute
Tel: +33. (0)18.104.22.168.94
Functional extracellular mitochondria revealed in the blood circulation. ©Alain R. Thierry/Inserm
Does the blood we thought to know so well contain elements that had been undetectable until now? The answer is yes, according to a team of researchers from Inserm, Université de Montpellier and the Montpellier Cancer Institute (ICM) working at the Montpellier Cancer Research Institute (IRCM), which has revealed the presence of whole functional mitochondria in the blood circulation. These organelles that are responsible for cellular respiration had hitherto only been found outside cells in very specific cases. The team’s findings, published in The FASEB Journal, will deepen our knowledge of physiology and open up new avenues for treatment.
Mitochondria are organelles that are found in the eukaryotic cells. A place of cellular respiration, they are the cells’ “batteries” and play a major role in energy metabolism and intercellular communication. Their particularity is to possess their own genome, transmitted solely by the mother and separate from the DNA contained in the nucleus. The mitochondria can sometimes be observed outside the cells in the form of fragments encapsulated within microvesicles. Under certain very specific conditions the platelets are also capable of releasing intact mitochondria into the extracellular space.
The researchers used previous findings which showed that the plasma of a healthy individual contains up to 50,000 times more mitochondrial DNA than nuclear DNA. They hypothesized that for it to be detectable and quantifiable in the blood in this manner, the mitochondrial DNA had to be protected by a structure of sufficient stability. In order to identify such a structure, plasma samples from around 100 individuals were analyzed.
This analysis revealed the presence in the blood circulation of highly stable structures containing whole mitochondrial genomes. Following examination of their size and density, as well as the integrity of their mitochondrial DNA, these structures observed using electron microscopy (up to 3.7 million per ml of plasma) were revealed to be intact and functional mitochondria.
Throughout the seven-year research period, the scientists used as many technical and methodological approaches as possible to validate this presence of circulating extracellular mitochondria in the blood.
“When we consider the sheer number of extracellular mitochondria found in the blood, we have to ask why such a discovery had not been made before, notes Thierry. Our team has built up expertise in the specific and sensitive detection of DNA in the blood, by working on the fragmentation of extracellular DNA derived from the mitochondria in particular”, he adds.
But what is the role of these extracellular mitochondria? The answer to that could be linked to the structure of the mitochondrial DNA, similar to that of bacterial DNA, which gives it the ability to induce immune and inflammatory responses. Based on this observation, the researchers hypothesize that these circulating mitochondria could be implicated in many physiological and/or pathological processes requiring communication between the cells (such as the mechanisms of inflammation). Indeed, recent studies have demonstrated the ability of certain cells to transfer mitochondria between themselves, such as the stem cells with damaged cells. “The extracellular mitochondria could perform various tasks as messenger for the entire body”, specifies Thierry.
This research is supported by the Montpellier Integrated Cancer Research Site (SIRIC) (Inserm/CNRS/Université de Montpellier/Montpellier Cancer Institute/Montpellier University Hospital/Université Paul Valéry), funded by Inserm, the National Cancer Institute (INCa) and the Directorate General of Health Care Provision (DGOS).
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Zahra Al Amir Dache1, Amaëlle Otandault1, Rita Tanos1, Brice Pastor1, Romain Meddeb1, Cynthia Sanchez1, Giuseppe Arena2, Laurence Lasorsa1, E. Andrew Bennett3, Thierry Grange3, Safia El Messaoudi1, Thibault Mazard1, Corinne Prevostel1, and Alain R. Thierry1
1 IRCM, Institut de Recherche en Cancérologie de Montpellier, Inserm U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
2 Gustave Roussy Cancer Campus, Inserm U1030, Villejuif 94805, France
3 Institut Jacques Monod, Université Paris Diderot, Paris, France
FASEB Journal: https://doi.org/10.1096/fj.201901917RR