April 24, 2017 Dr. Meng Wang is an associate professor of the Huffington Center On Aging at Baylor College of Medicine. Credit: Baylor College of Medicine

Researchers at Baylor College of Medicine have uncovered a new mechanism showing how microbes can alter the physiology of the organisms in which they live. In a paper published in Nature Cell Biology, the researchers reveal how microbes living inside the laboratory worm C. elegans respond to environmental changes and generate signals to the worm that alter the way it stores lipids.

"Microbe-host interactions have been known for a long time, but the actual molecular mechanisms that mediate the interactions were largely unknown," said senior author Dr. Meng Wang, associate professor of molecular and human genetics at Baylor and the Huffington Center On Aging. "Microbes living inside another organism, the host, can respond to changes in the environment, change the molecules they produce and consequently influence the normal workings of the host's body, including disease susceptibility."

In this study, Wang and first author Dr. Chih-Chun Lin working in the Wang Lab have dissected for the first time a molecular mechanism by which E. coli bacteria can regulate C. elegans' lipid storage.

How E. coli changes lipid storage in C. elegans

C. elegans is a laboratory worm model scientists use to study basic biological mechanisms in health and disease.

"This worm naturally consumes and lives with bacteria in its gut and interacts with them in ways that are similar to those between humans and microbes. In the laboratory, we can study basic biological mechanisms by controlling the type of bacteria living inside this worm as well as other variables and then determining the effect on the worm's physiology," Wang said.

In this study, Wang and Lin compared two groups of worms. One group received bacteria that had been grown in a nutritionally rich environment. The other group of worms received the same type of bacteria, but it had grown in nutritionally poor conditions. Both groups of worms received the same amount and type of nutrients, the only difference was the type of environment in which the bacteria had grown before they were administered to the worms.

Interestingly, the worms carrying bacteria that came from a nutritionally poor environment had in their bodies twice the amount of fat present in the worms living with the bacteria coming from the nutritionally rich environment.

The researchers then carried out more experiments and determined that it was the lack of the amino acid methionine in the nutritionally poor environment that had triggered the bacteria to adapt by producing different compounds that then initiated a cascade of events in the worm that led to extra fat accumulation. In addition, the researchers observed that the tissues showing extra fat accumulation also had their mitochondria fragmented. The activities of the mitochondria, the balance between their fusion and breaking apart, are known to be tightly coupled with metabolic activities.

A mechanism that reveals unsuspected connections

The researchers found that the bacteria were able to trigger mitochondrial fragmentation and then extra lipid accumulation because the molecular intermediates the bacteria had triggered allowed them to 'establish communication' with the mitochondria.

"We have found evidence for the first time that bacteria and mitochondria can 'talk to each other' at the metabolic level," Wang said.

Bacteria and mitochondria are like distant relatives. Evolutionary evidence strongly suggests that mitochondria descend from bacteria that entered other cell types and became incorporated into their structure. Mitochondria play essential roles in many aspects of the cell's metabolism, but also maintain genes very similar to those of their bacterial ancestors.

"It's interesting that the molecules bacteria generate can chime in the communication between mitochondria and regulate their fusion-fission balance," Wang said. "Our findings reveal this kind of common language between bacteria and mitochondria, despite them being evolutionary distant from each other."

Some components of this common language involve proteins such as NR5A, Patched and Sonic Hedgehog. The latter is of particular interest to the researchers because it has not been involved in regulating lipid metabolism and mitochondrial dynamics before.

"Microbes in the microbiome can affect many aspects of their host's functions, and here we present a new molecular mechanism mediating microbe-host communication," Wang said. "Having discovered one mechanism encourages us to investigate others that may be related to other physiological aspects, such as the stress response and aging, among others."

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More information: Microbial metabolites regulate host lipid metabolism through NR5AHedgehog signalling, Nature Cell Biology (2017). nature.com/articles/doi:10.1038/ncb3515

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Scientists reveal a new mechanism mediating environment-microbe-host interactions - Phys.Org

As they find out more about the cell biology of multiple sclerosis, scientists are gradually unraveling the mysteries of the disease, although the exact causes are still unclear. Now, a new study continues this progress with a significant discovery about a new cellular mechanism. It suggests that high levels of the protein Rab32 disrupt key communications involving mitochondria. The disruption causes these "cellular batteries" to misbehave, leading to the toxic effects seen in the brain cells of people with multiple sclerosis.

The new study is the work of researchers from the University of Exeter in the United Kingdom and the University of Alberta in Canada. They report their findings in the Journal of Neuroinflammation.

Co-author Paul Eggleton, an immunologist and professor at the University of Exeter Medical School, says that multiple sclerosis can have a "devastating impact on people's lives," and yet, unfortunately, the present situation is that "all medicine can offer is treatment and therapy for the symptoms."

Multiple sclerosis (MS) is a disease in which the immune system mistakenly attacks tissue of the central nervous system - which comprises the brain, spinal cord, and optic nerve.

As the disease progresses, it destroys more and more of the fatty myelin sheath that insulates and protects the nerve fibers that send electrical messages in the central nervous system.

This destruction can lead to brain damage, vision impairment, pain, altered sensation, extreme fatigue, problems with movement, and other symptoms.

As research into the cause of MS progresses, scientists are becoming increasingly interested in the role of mitochondria - the tiny components inside cells that produce units of energy for powering the cell.

Fast facts about MS

Learn more about MS

In earlier work, the team behind the new study was the first to provide an explanation for the role of defective mitochondria in MS through clinical and laboratory experiments.

In their new investigation, the researchers study a protein called Rab32, which is known to be involved in certain mitochondrial processes.

They found that levels of Rab32 are much higher in the brains of people with MS and hardly detectable in brains of people without the disease.

They also discovered that the presence of Rab32 coincides with disruption to a communication system that causes mitochondria to malfunction, causing toxic effects in the brain cells of people with MS.

The disruption is caused by a cell compartment called the endoplasmic reticulum (ER) being too close to the mitochondria.

The ER produces, processes, and transports many compounds that are used inside and outside the cell.

The researchers note that one of the functions of the ER is to store calcium, and if the distance between the ER and mitochondria is too short, it disrupts the communication between the mitochondria and the calcium supply.

Calcium uptake into mitochondria is already known to be critical to cell functioning.

Although they did not discover what causes Rab32 levels to increase, the team believes that the problem may lie in a defect in the base of the ER.

The study could help scientists to find ways to use Rab32 as a treatment target, as well as look for other proteins that may cause similar disruptions, note the authors.

"Our exciting new findings have uncovered a new avenue for researchers to explore. It is a critical step, and in time, we hope it might lead to effective new treatments for MS."

Prof. Paul Eggleton

Learn how a new immunotherapy reversed paralysis in mouse models of MS.

Read more:
Scientists step closer to finding cause of multiple sclerosis - Medical News Today

April 24, 2017 During cell division, DNA must be copied and distributed between daughter cells. A cellular structure called the mitotic spindle pulls apart the DNA-containing structures, the chromosomes. The photo shows a microscopic image of DNA (blue) in a spindle. The protein ASPM appears to play a key role in this process, as it is located at the 'poles' (yellow) in the spindle. Credit: Cell Biology Utrecht University

Two years ago, the Zika virus drew attention to microcephaly, a developmental disorder in which the brain and skull display inhibited growth. But there are other causes of microcephaly, such as congenital genetic diseases. Much is still unknown about brain development, but researchers at Utrecht University, in collaboration with their colleagues in Switzerland, have now new shed light on the molecules involved. The results of their research will be published in Nature Cell Biology.

"Biological processes are determined by molecules in our cells. We can only understand the factors that determine health and disease and find medicines to control these factors by zooming into this molecular world", explains research leader Prof. Anna Akhmanova.

Surprising discovery

The researchers began their studies by focusing on the protein ASPM. "We knew that the genetic form of microcephaly is most often caused by defects in this protein. But a surprising discovery was that ASPM appears to work closely together with another protein, called katanin", tells Akhmanova.

Essential for healthy development

It appears that precisely this collaboration is important for cell division, and therefore for the normal development of brain cells. "The interaction between ASPM and katanin is required for the proper balance between cell division and their specialisation into nerve cells. When the balance sways too much in one direction or the other, too few brain cells are produced", Akhmanova adds.

Crucial balance

For developing brain cells, this balance is especially crucial, because once they become nerve cells, they cannot divide. If new cells develop into nerve cells too quickly, not enough cells are formed, and the brain remains small.

Key position

During cell division, DNA must be copied and distributed between daughter cells. A cellular structure called the mitotic spindle pulls apart the DNA-containing structures, the chromosomes. The photo shows a microscopic image of DNA (blue) in a spindle. The protein ASPM appears to play a key role in this process, as it is located at the 'poles' (yellow) in the spindle.

Spindle position

The study shows how ASPM does its work at the molecular level, and why it is so important. In cooperation with the protein katanin, ASPM is responsible for the regulation of the organisation and positioning of the spindle. "It is this positioning that helps to determine how the daughter cells develop: will they become copies of new cells, or will they develop into nerve cells", Akhmanova explains.

Much broader insight

The fact that a deviation in the protein ASPM leads to microcephaly can now be better understood at the molecular level. However, the results of this study provide a much broader insight, which may make it possible to explain or find other causes of the disorder.

Evolutionarily unique

Akhmanova's fascination for brain development is not limited to disease, however. "Even apes, our closest relatives, have much less brain capacity than we do. Our brain makes us what we are. This means the development of our brain is evolutionarily very special."

Explore further: Scientists uncover how Zika virus causes microcephaly

More information: Microtubule minus-end regulation at spindle poles by an ASPMkatanin complex, Nature Cell Biology (2017). nature.com/articles/doi:10.1038/ncb3511

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