Unexpected insights into the dynamic structure of mitochondria

As power plants and energy stores, mitochondria are essential components of almost all cells in plants, fungi and animals. Until now, it has been assumed that these functions underlie a static structure of mitochondrial membranes. Researchers at the Heinrich Heine University Düsseldorf (HHU) and the University of California Los Angeles (UCLA), supported also by the Center for Advanced Imaging (CAi) of HHU, and have now discovered that the inner membranes of mitochondria are by no means static, but rather constantly change their structure every few seconds in living cells. This dynamic adaptation process further increases the performance of our cellular power plants. "In our opinion, this finding fundamentally changes the way our cellular power plants work and will probably change the textbooks," says Prof. Dr. Andreas Reichert, Institute of Biochemistry and Molecular Biology I at the HHU. The results are described in a publication in EMBO Reports.

Mitochondria are extremely important components in cells performing vital functions including the regulated conversion of energy from food into chemical energy in the form of ATP. ATP is the energy currency of cells and an adult human being produces (and consumes) approximately 75 kilograms of ATP per day. One molecule of ATP is produced about 20,000 times a day and then consumed again for energy utilization. This immense synthesis capacity takes place in the inner membrane of the mitochondria, which has numerous folds called cristae. It was previously assumed that a specific static structure of the cristae ensured the synthesis of ATP. Whether and to what extent cristae membranes are able to dynamically adapt or alter their structure in living cells and which proteins are required to do so, was unknown.

The research team of Prof. Dr. Andreas Reichert with Dr. Arun Kondadi and Dr. Ruchika Anand from the Institute of Biochemistry and Molecular Biology I of the HHU in collaboration with the research team of Prof. Dr. Orian Shirihai and Prof. Dr. Marc Liesa from UCLA (USA) succeeded for the first time in showing that cristae membranes in living cells continuously change their structure dynamically within seconds within mitochondria. This showed that the cristae membrane dynamics requires a recently identified protein complex, the MICOS complex. Malfunctions of the MICOS complex can lead to various serious diseases, such as Parkinson's disease and a form of mitochondrial encephalopathy with liver damage. After the identification of the first protein component of this complex (Fcj1/Mic60) about ten years ago by Prof. Andreas Reichert and his research group, this is another important step to elucidate the function of the MICOS complex.

"Our now published observations lead to the model that cristae, after membrane fission, can exist for a short time as isolated vesicles within mitochondria and then re-fuse with the inner membrane. This enables an optimal and extremely rapid adaptation to the energetic requirements in a cell," said Prof. Andreas Reichert.

News source: https://phys.org/news/

More information: Arun Kumar Kondadi et al, Cristae undergo continuous cycles of membrane remodelling in a MICOS ‐dependent manner, EMBO Reports (2020). DOI: 10.15252/embr.201949776

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

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