A New Blood Component Revealed

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 work of a team led by Inserm researcher Alain R. Thierry at the Montpellier Cancer Research Institute (Inserm/Université de Montpellier/Montpellier Cancer Institute) has now revolutionized knowledge of this organelle by revealing that whole functioning extracellular mitochondria are in fact found in the bloodstream!

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.

In addition to its importance to our knowledge of physiology, this discovery could lead to improvements in the diagnosis, monitoring and treatment of certain diseases. In fact, the research team is now devoting its attention to evaluating the extracellular mitochondria as biomarkers in non-invasive prenatal diagnosis and cancer.

Inserm press room A New Blood Component Revealed
Link : https://presse.inserm.fr/en/a-new-blood-component-revealed/37905/

Breakthrough in Understanding Evolution – Mitochondrial Division Conserved Across Species

New study shows exactly how the manner in which mitochondria divide has remained the same since evolution began.

Cellular origin is well explained by the “endosymbiotic theory,” which famously states that higher organisms called “eukaryotes” have evolved from more primitive single-celled organisms called “prokaryotes.” This theory also explains that mitochondria—energy-producing factories of the cell—are actually derived from prokaryotic bacteria, as part of a process called “endosymbiosis.” Biologists believe that their common ancestry is why the structure of mitochondria is “conserved” in eukaryotes, meaning that it is very similar across different species—from the simplest to most complex organisms. Now, it is known that as cells divide, so do mitochondria, but exactly how mitochondrial division takes place remains a mystery. Is it possible that mitochondria across different multicellular organisms—owing to their shared ancestry—divide in an identical manner? Considering that mitochondria are involved in some of the most crucial processes in the cell, including the maintenance of cellular metabolism, finding the answer to exactly how they replicate could spur further advancements in cell biology research.

In a new study published in Communications Biology on December 20, 2019, a group of scientists at Tokyo University of Science, led by Prof Sachihiro Matsunaga, wanted to find answers related to the origin of mitochondrial division. For their research, Prof Matsunaga and his team chose to study a type of red alga—the simplest form of a eukaryote, containing only one mitochondrion. Specifically, they wanted to observe whether the machinery involved in mitochondrial replication is conserved across different species and, if so, why. Talking about the motivation for this study, Prof Matsunaga says, “Mitochondria are important to cellular processes, as they supply energy for vital activities. It is established that cell division is accompanied by mitochondrial division; however, many points regarding its molecular mechanism are unclear.”

This exciting new research describes how mitochondrial replication is similar in the simplest to most complex organisms, shedding light on its origin. Credit: Tokyo University of Science

The scientists first focused on an enzyme called Aurora kinase, which is known to activate several proteins involved in cell division by “phosphorylating” them (a well-known process in which phosphate groups are added to proteins to regulate their functions). By using techniques such as immunoblotting and kinase assays, they showed that the Aurora kinase in red algae phosphorylates a protein called dynamin, which is involved in mitochondrial division. Excited about these findings, Prof Matsunaga and his team wanted to take their research to the next level by identifying the exact sites where Aurora kinase phosphorylates dynamin, and using mass spectrometric experiments, they succeeded in identifying four such sites. Prof Matsunaga says, “When we looked for proteins phosphorylated by Aurora kinase, we were surprised to find dynamin, a protein that constricts mitochondria and promotes mitochondrial division.”

Having gained a little more insight into how mitochondria divide in red algae, the scientists then wondered if the process could be similar in more evolved eukaryotes, such as humans. Prof Matsunaga and his team then used a human version of Aurora kinase to see if it phosphorylates human dynamin—and just as they predicted, it did. This led them to conclude that the process by which mitochondria replicate is very similar in different eukaryotic organisms. Prof Matsunaga elaborates on the findings by saying, “Using biochemical in vitro assays, we showed that Aurora kinase phosphorylates dynamin in human cells. In other words, it was found that the mechanism by which Aurora kinase phosphorylates dynamin in the mitochondrion is preserved from primitive algae to humans.”

Scientists have long pondered over the idea of mitochondrial division being conserved in eukaryotes. This study is the first to show not only the role of a new enzyme in mitochondrial replication but also that this process is similar in both algae and humans, hinting towards the fact that their common ancestry might have something to do with this. Prof Matsunaga concludes by talking about the potential implications of this study, “Since the mitochondrial fission system found in primitive algae may be preserved in all living organisms including humans, the development of this method can make it easier to manipulate cellular activities of various organisms, as and when required.”

As it turns out, we have much more in common with other species than we thought, and part of the evidence lies in our mitochondria!

Reference: “Cyanidioschyzon merolae aurora kinase phosphorylates evolutionarily conserved sites on its target to regulate mitochondrial division” by Shoichi Kato, Erika Okamura, Tomoko M. Matsunaga, Minami Nakayama, Yuki Kawanishi, Takako Ichinose, Atsuko H. Iwane, Takuya Sakamoto, Yuuta Imoto, Mio Ohnuma, Yuko Nomura, Hirofumi Nakagami, Haruko Kuroiwa, Tsuneyoshi Kuroiwa and Sachihiro Matsunaga, 20 December 2019, Communications Biology.
DOI: 10.1038/s42003-019-0714-x

News Source: https://scitechdaily.com

A protein found in ovarian cancer may contribute to neurodegeneration in Alzheimer's disease

Houston Methodist scientists identified a protein found in ovarian cancer that may contribute to declining brain function and Alzheimer's disease, by combining computational methods and lab research.

In a study published online in the journal EBiomedicine, Wong and his team at the Ting Tsung and Wei Fong Chao Center for BRAIN of Houston Methodist, reported on a new role of OCIAD1 (ovarian cancer immune-reactive antigen domain containing 1). Originally discovered for its effect on ovarian cancer metastasis and stem cell metabolisms, Wong's group found the OCIAD1 protein in human brain cells--and determined it impairs neurons and damages synapses in the brain, contributing to neurodegeneration in Alzheimer's disease.

"Our research addresses a fundamental question of Alzheimer's disease-;how, or if, amyloid beta accumulation that can be seen up to two decades prior to brain function decline is involved in progressive neurodegeneration," said Wong, who is John S Dunn Sr. presidential distinguished chair in biomedical engineering and professor of computer science and bioengineering in oncology at Houston Methodist. "Examining factors that contribute to the progressive decline in people with Alzheimer's will help us develop diagnostic biomarkers and new therapeutics."

The scientists culled through archived bioinformatics data of brain tissue from deceased Alzheimer's patients, as well as mouse models by blending computational methods with laboratory research. They determined that OCIAD1 plays a role in the disease's progressive neurodegeneration by impairing mitochondria function. Known as the powerhouse of cells, damage to mitochondria results in the trickle-down cell death effect in the brain leading to neuron damage.

"We applied a system biology strategy to see if we could find a different mechanism of neurodegeneration in Alzheimer's disease. We identified OCIAD1 as a new neurodegeneration-relevant factor, predicted its function, and demonstrated it mediates the long-term impact of amyloid beta on cells and synaptic damages by impairing mitochondria function," said Xuping Li, Ph.D., co-corresponding author and an instructor in Wong's group.

Alzheimer's research has traditionally focused on a few major themes - the role of the amyloid protein on neuronal loss and how this toxic protein causes injury by interacting with tau. More recently, however, other research considers amyloid beta a bystander and questions whether it causes neuronal degeneration at all.

The epidemic of Alzheimer's, a disease affecting more than 5.8 million Americans, is expected to increase as the aging population lives longer. According to the Alzheimer's Association and the Center for Disease Control and Prevention, Alzheimer's is the most expensive disease in the United States, costing an estimated $290 billion in 2019.

News Source: www.news-medical.net

Salk researchers uncover new function of mitochondria

Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.

Most of the DNA that a cell needs to function is found inside the cell's nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds--or even thousands--of mitochondria.

Shadel's lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus--by releasing it from mitochondria and launching an immune response that beefs up the cell's defenses.

In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell's interior. They homed in on a subset of genes known as interferon-stimulated genes, or ISGs, that are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.

To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage--and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell's DNA.

"Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress," says Shadel.

Most of the time, he points out, it's probably a good thing that the mtDNA is more prone to damage--it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin--by damaging mtDNA first and setting off molecular alarm bells--can be less effective at damaging the nuclear DNA of cancer cells.

"It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance," Shadel says.

His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell's nucleus to ward off damage.