GN/ Damage to cell membranes may induce cell aging
Genetics biweekly vol.52, 15th February — 1st March
TL;DR
- Researchers have discovered that damage to the cell membrane promotes cellular senescence, or cell aging.
- Innovations in disease treatment involve harnessing the cell’s waste disposal system to eradicate harmful proteins, presenting a novel approach beyond enzyme inhibition.
- Sea lampreys, ancient creatures with a fearsome reputation, share a remarkably similar molecular and genetic toolkit in their hindbrain with humans, shedding light on evolutionary connections.
- Consuming over 22% of dietary calories from protein may activate immune cells linked to atherosclerotic plaque formation, increasing disease risk, according to a recent study.
- A pharmacy associate professor develops nanomedicine loaded with small interfering RNAs (siRNA) for gene therapy against human immunodeficiency virus (HIV).
- Researchers discover a signal from sperm that triggers cell division in plants, potentially allowing for deliberate activation without fertilization and opening avenues for asexual propagation of crop plants.
- The quality of tea is influenced by the collection of microbes on tea roots, as altering this assemblage can enhance the taste of tea, according to a new study.
- Mice receiving fecal implants from donors with ovaries removed show increased fat mass and expression of genes associated with inflammation and metabolic dysfunction, offering insights into postmenopausal women’s health.
- Identification of a protein complex activated by spliceosome defects suggests potential therapeutic approaches for diseases caused by faulty splicing.
- New findings reveal a mode of force transmission involving dynamic molecular stretching bridging the extracellular matrix and flowing F-actin, emphasizing the role of molecular elasticity and random coupling in force transmission.
- And more!
Overview
Genetic technology is defined as the term that includes a range of activities concerned with the understanding of gene expression, advantages of natural genetic variation, modifying genes and transferring genes to new hosts. Genes are found in all living organisms and are transferred from one generation to the next. Gene technology encompasses several techniques including marker-assisted breeding, RNAi, and genetic modification. Only some gene technologies produce genetically modified organisms.
Modern genetic technologies like genome editing would not be possible without all the previous generations of genetic technologies that have enabled scientists to discover what genes are, what they do, and how DNA can be modified to add, remove, or replace genes. You can find major genetic technologies development milestones via the link.
Gene Technology Market
- The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.
- Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).
- North America holds the largest share of the global genetic engineering market, followed by Europe and the Asia Pacific, respectively.
Latest News & Research
Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts
by Kojiro Suda, Yohsuke Moriyama, Nurhanani Razali, Yatzu Chiu, Yumiko Masukagami, Koutarou Nishimura, Hunter Barbee, Hiroshi Takase, Shinju Sugiyama, Yuta Yamazaki, Yoshikatsu Sato, Tetsuya Higashiyama, Yoshikazu Johmura, Makoto Nakanishi, Keiko Kono in Nature Aging
Our cells are surrounded by a fragile membrane that’s only 5 nanometers thick, 1/20 of a soap bubble. Cells are easily damaged by physiological activities, including muscle contraction and tissue injury. To cope with such damage, cells are equipped with mechanisms that can repair membrane damage to a certain degree.
Mechanical damage to the cell membrane was previously believed to trigger two simple cellular outcomes: recovery or death. In this study, however, the researchers uncovered a third outcome — cellular senescence.
“When I started this project, I simply aimed to understand the repair mechanisms of damaged cell membrane,” recalls Professor Keiko Kono, head of the Membranology unit and senior author of this study, which involved multiple members from the unit, including Kojiro Suda, Yohsuke Moriyama, Nurhanani Razali and colleagues.
“Unexpectedly, we ended up discovering that cell membrane damage, in a sense, switches cell fate.”
The key to determining cell fate is the extent of damage and subsequent calcium ion influx. The thin cell membrane damage can be easily repaired, allowing the cells to continue cell division without any trouble.
The highest level of cell membrane damage induces cell death. However, a middle level of cell membrane damage turns the cells into senescent cells several days later, even though membrane resealing seems successful.
Cancer cells divide unlimitedly. In contrast, non-cancerous normal cells have a limited capacity for cell division — around 50 times before division is irreversibly stopped, and the cells enter a state known as cellular senescence. Senescent cells are still metabolically active, but unlike young and healthy cells, they produce various secretory proteins that upregulate immune responses in both nearby tissues and distant organs. This mechanism can induce both beneficial and detrimental changes in our body, including acceleration of wound healing, cancer promotion, and aging.
During the last decade, numerous studies have reported that senescent cells exist in animal bodies, including humans, and that the removal of senescent cells can rejuvenate body functions in experimental animals. However, the cause of cell senescence in the human body remains a controversial topic.
“The gene expression profile and bioinformatics suggested that cell membrane damage explains the origin of senescent cells in our bodies, specifically the ones near damaged tissues,” explains Professor Kono.
The best-established inducer of cellular senescence is repeated cell division. Many other stresses also induce cellular senescence in a laboratory setting, such as DNA damage, oncogene activation, and epigenetic changes. The long-standing dogma in the research field was that various stresses induce cellular senescence ultimately via the activation of DNA damage response. However, the authors uncovered that cell membrane damage induces cellular senescence via a different mechanism that involves calcium ions and the tumor suppressor gene p53. These findings may contribute to develop a strategy to achieve healthy longevity in the future.
Targeted protein degradation via intramolecular bivalent glues
by Oliver Hsia, Matthias Hinterndorfer, Angus D. Cowan, Kentaro Iso, Tasuku Ishida, Ramasubramanian Sundaramoorthy, Mark A. Nakasone, Hana Imrichova, Caroline Schätz, Andrea Rukavina, Koraljka Husnjak, Martin Wegner, Alejandro Correa-Sáez, Conner Craigon, Ryan Casement, Chiara Maniaci, Andrea Testa, Manuel Kaulich, Ivan Dikic, Georg E. Winter, Alessio Ciulli in Nature
Established treatments for cancer and other diseases often focus on inhibiting harmful enzymes to mitigate their effects. However, a more innovative approach has emerged: harnessing the cell’s natural waste disposal system not just to deactivate but to entirely eradicate these proteins. Researchers at CeMM have already demonstrated the efficacy of this approach through two distinct methods. Now, in collaboration with colleagues from the University of Dundee in Scotland, they unveil a third system capable of targeting and disposing of previously inaccessible proteins.
Living cells resemble highly organized small towns — in addition to energy production, transportation systems, and construction, cells also require efficient waste disposal. Most proteins, which shape and sustain cellular function, have only a limited half-life and must eventually be disposed of, along with defective and unwanted proteins. This vital task falls upon specialized enzymes known as ubiquitin ligases, which tag obsolete proteins for degradation, guiding them to the cellular recycling center, the proteasome.
Ubiquitin, acting as molecular label, ensures the targeted proteins are efficiently processed for disposal. Yet, cells are not always able to recognize and mark every harmful protein with ubiquitin accordingly. Many diseases such as cancer or neurodegenerative diseases like Alzheimer’s can only arise because harmful proteins accumulate in cells. This is where the research of Georg Winter’s group at CeMM comes in: with a technique called “targeted protein degradation,” harmful or otherwise unwanted proteins can be marked with ubiquitin and destroyed in the proteasome, effectively reprogramming the cell’s waste disposal system.
So far, this has worked in one of two ways: either by introducing a chemical agent (so-called PROTACs) into the cell, which attaches to one side of the protein to be degraded and to the ubiquitin ligase on the other side, thereby directly linking the two and marking the undesired protein for degradation. Or, by introducing a kind of “molecular glue” into the cell, which attaches to the ligase and thereby induces it to recognize and mark the unwanted protein for degradation.
In the new study, the team led by Georg Winter (CeMM) and Alessio Ciulli (University of Dundee) has revealed a third way that combines both of these existing strategies: so-called “intramolecular bivalent glues” (IBGs) attach to two points on the protein to be degraded, slightly bending it and thereby altering its surface. This alteration is recognized by a ubiquitin ligase, thus marking the protein for degradation.
“This method opens up completely new possibilities for the development of drugs that can be used against cancer, among other diseases” says Georg Winter. “Together with other targeted protein degradation methods, this could potentially treat many diseases that have previously been undruggable.”
“So far, we often discover drugs that lead to targeted protein degradation only by chance. However, the better we understand how this system works, the closer we come to being able to design such drugs deliberately,” says Matthias Hinterndorfer, a postdoctoral researcher in Georg Winter’s research group. Therefore, the new discovery provides important insights into the mechanisms and therapeutic opportunities of targeted protein degradation.
Sea lamprey enlightens the origin of the coupling of retinoic acid signaling to vertebrate hindbrain segmentation
by Alice M. H. Bedois, Hugo J. Parker, Andrew J. Price, Jason A. Morrison, Marianne E. Bronner, Robb Krumlauf in Nature Communications
The sea lamprey, a 500-million-year-old animal with a sharp-toothed suction cup for a mouth, is the thing of nightmares. A new study from the Stowers Institute for Medical Research discovered that the hindbrain — the part of the brain controlling vital functions like blood pressure and heart rate — of both sea lampreys and humans is built using an extraordinarily similar molecular and genetic toolkit.
Research from the lab of Investigator Robb Krumlauf, Ph.D. offers a glimpse into how the brains of ancient animals evolved. The team unexpectedly uncovered that a crucial molecular cue is very broadly required during vertebrate hindbrain development.
“This study on the hindbrain is essentially a window into the distant past and serves as a model for understanding the evolution of complexity,” said co-author Hugo Parker, Ph.D.
Like other vertebrate animals, sea lampreys have a backbone and skeleton, but they are noticeably missing a feature of their heads — a jaw. Because most vertebrates, including humans, have jaws, this striking difference in sea lampreys makes them valuable models for understanding the evolution of vertebrate traits.
“There was a split at the origin of vertebrates between jawless and jawed around 500 million years ago,” said Alice Bedois, Ph.D., a former predoctoral researcher in the Krumlauf Lab and lead author on the study. “We wanted to understand how the vertebrate brain evolved and if there was something unique to jawed vertebrates that was lacking in their jawless relatives.”
Previous work from the Krumlauf Lab and the lab of Marianne Bronner, Ph.D., at the California Institute of Technology had identified that the genes structuring and subdividing the sea lamprey hindbrain are identical to those in jawed vertebrates including humans. However, these genes are part of an interconnected network or circuit that needs to be initiated and directed to build the hindbrain correctly. The new study identified a common molecular cue, while known to direct head-to-tail patterning in a wide variety of animals, as part of the gene circuitry guiding hindbrain patterning in sea lampreys.
“We found that not only are the same genes but also the same cue is involved in sea lamprey hindbrain development, suggesting this process is ancestral to all vertebrates,” said Bedois.
This cue is called retinoic acid, commonly known as vitamin A. While the researchers knew that retinoic acid cues the gene circuitry to build the hindbrain in complex species, it was not thought to be involved for more primitive animals like sea lampreys. Surprisingly, they found that the sea lamprey core hindbrain circuit is also initiated by retinoic acid, providing evidence that these sea monsters and humans are much more closely related than anticipated.
“People thought that because sea lampreys lack a jaw, their hindbrain was not formed like other vertebrates,” said Krumlauf. “We have shown that this basic part of the brain is built in exactly the same way as mice and even humans.”
There are well known signaling molecules that inform the fate of cells during development. Now, the researchers have found that retinoic acid is another major player that cues vital steps in development like formation of the brain stem. In addition, if hindbrain formation is a conserved feature for all vertebrates, other mechanisms must be responsible to explain their incredible diversity.
“We all derived from a common ancestor,” said Bedois. “Sea lampreys have provided an additional clue. Now we need to look even further back in evolutionary time to discover when the gene circuitry governing hindbrain formation first evolved.”
Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk
by Zhang, X., Kapoor, D., Jeong, SJ. et al. in Nat Metab
University of Pittsburgh School of Medicine researchers discovered a molecular mechanism by which excessive dietary protein could increase atherosclerosis risk.
The study, which combined small human trials with experiments in mice and cells in a Petri dish, showed that consuming over 22% of dietary calories from protein can lead to increased activation of immune cells that play a role in atherosclerotic plaque formation, driving the disease risk. Furthermore, the scientists showed that one amino acid — leucine — seems to have a disproportionate role in driving the pathological pathways linked to atherosclerosis, or stiff, hardened arteries.
“Our study shows that dialing up your protein intake in pursuit of better metabolic health is not a panacea. You could be doing real damage to your arteries,” said senior and co-corresponding author Babak Razani, M.D., Ph.D., professor of cardiology at Pitt.
“Our hope is that this research starts a conversation about ways of modifying diets in a precise manner that can influence body function at a molecular level and dampen disease risks.”
According to a survey of an average American diet over the last decade, Americans generally consume a lot of protein, mostly from animal sources. Further, nearly a quarter of the population receives over 22% of all daily calories from protein alone. That trend is likely driven by the popular idea that dietary protein is essential to healthy living, says Razani. But his and other groups have shown that overreliance on protein may not be such a good thing for long-term health.
Following their 2020 research, in which Razani’s laboratory first showed that excess dietary protein increases atherosclerosis risk in mice, his next study in collaboration with Bettina Mittendorfer, Ph.D., a metabolism expert at the University of Missouri, Columbia, delved deeper into the potential mechanism and its relevance to the human body. To arrive at the answer, Razani’s laboratory, led by first-authors Xiangyu Zhang, Ph.D., and Divya Kapoor, M.D., teamed up with Mittendorfer’s group to combine their expertise in cellular biology and metabolism and perform a series of experiments across various models — from cells to mice to humans.
“We have shown in our mechanistic studies that amino acids, which are really the building blocks of the protein, can trigger disease through specific signaling mechanisms and then also alter the metabolism of these cells,” Mittendorfer said. “For instance, small immune cells in the vasculature called macrophages can trigger the development of atherosclerosis.”
Based on initial experiments in healthy human subjects to determine the timeline of immune cell activation following ingestion of protein-enriched meals, the researchers simulated similar conditions in mice and in human macrophages, immune cells that are shown to be particularly sensitive to amino acids derived from protein. Their work showed that consuming more than 22% of daily dietary calories through protein can negatively affect macrophages that are responsible for clearing out cellular debris, leading to the accumulation of a “graveyard” of those cells inside the vessel walls and worsening of atherosclerotic plaques overtime.
Interestingly, the analysis of circulating amino acids showed that leucine — an amino acid enriched in animal-derived foods like beef, eggs and milk — is primarily responsible for abnormal macrophage activation and atherosclerosis risk, suggesting a potential avenue for further research on personalized diet modification, or “precision nutrition.”
Razani is careful to note that many questions remain to be answered, mainly: What happens when a person consumes between 15% of daily calories from protein as recommended by the USDA and 22% of daily calories from protein, and if there is a ‘sweet spot’ for maximizing the benefits of protein — such as muscle gain — while avoiding kick-starting a molecular cascade of damaging events leading to cardiovascular disease.
The findings are particularly relevant in hospital settings, where nutritionists often recommend protein-rich foods for the sickest patients to preserve muscle mass and strength.
“Perhaps blindly increasing protein load is wrong,” Razani said. “Instead, it’s important to look at the diet as a whole and suggest balanced meals that won’t inadvertently exacerbate cardiovascular conditions, especially in people at risk of heart disease and vessel disorders.”
Razani also notes that these findings suggest differences in leucine levels between diets enriched in plant and animal protein might explain the differences in their effect on cardiovascular and metabolic health.
“The potential for this type of mechanistic research to inform future dietary guidelines is quite exciting,” he said.
pH-sensitive dual-preventive siRNA-based nanomicrobicide reactivates autophagy and inhibits HIV infection in vaginal CD4+ cells
by Sidi Yang, Yufei Chen, Jijin Gu, Angela Harris, Ruey-Chyi Su, Emmanuel A. Ho in Journal of Controlled Release
Society learned about the value of mRNA during the COVID-19 pandemic when we saw scientists and medical professionals harness its power to deliver a vaccine for the virus within a year.
Now, University of Waterloo pharmacy associate professor Emmanuel Ho has developed a novel nanomedicine loaded with genetic material called small interfering RNAs (siRNA) to fight human immunodeficiency virus (HIV) using gene therapy. These siRNAs regulate which genes or proteins are turned on or off in our cells and showed a 73 per cent reduction in HIV replication.
“This opens the door for new therapeutics in the fight against HIV,” said Dr. Ho, who is among Waterloo’s researchers and entrepreneurs leading health innovation in Canada.
Autophagy, also known as the body’s recycling process, plays an important role in our body to eliminate microbes such as viruses and bacteria inside cells. HIV is quite smart and produces a protein, Nef, that prevents cells from activating autophagy. This is the first research to develop a combination nanomedicine that can reactivate autophagy and prevent HIV entry into cells, allowing our body to re-initiate its defence system. Additionally, HIV has a gene, CCR5, that allows the virus to enter a cell. The siRNAs target both Nef and CCR5 to reduce HIV infection.
This nanomedicine is intended to be applied vaginally to protect against sexual transmission of HIV. As a result, the nanomedicine is designed to be stable without leakage of siRNAs in the acidic vaginal environment but release the siRNA once inside cells.
“Viruses are smart. They produce Nef proteins to prevent autophagy from occurring,” Ho said. “Our process allows our body to fight the viral infection without needing additional drugs,”
Ho confirms that the next steps include further optimizing the process and improving our understanding of how autophagy plays a role in how our cells protect us from viruses.
“We also hope this will shed some light to develop more alternative approaches to effectively reduce antimicrobial resistance,” Ho said.
A paternal signal induces endosperm proliferation upon fertilization in Arabidopsis
by Sara Simonini, Stefano Bencivenga, Ueli Grossniklaus in Science
Seeds are the end product of plant reproduction. Whether directly as food, or indirectly as animal feed, they provide around 80 percent of human calorie consumption. In the millennia since humans first settled, we have bred countless plant varieties with advantageous characteristics, such as increased yields, improved quality, resistance to pests or hardiness. Where possible, farmers use hybrid varieties, which are created by crossing two inbred lines and are more resistant and higher-yielding than normal varieties. The problem is that these desired properties are lost during propagation and, therefore, hybrid seeds have to be recreated every year.
If we could find a way to propagate crop plants by asexual reproduction through seeds — known as apomixis — it would revolutionize agriculture. If it were possible to bypass the reductional division and fertilization of female gametes, the seeds produced would be genetically identical to the mother plant. Plant varieties with desired characteristics could thus be propagated much more easily — as seed clones. Now, Ueli Grossniklaus and his team at the Department of Plant and Microbial Biology at the University of Zurich (UZH) have come a step closer to achieving this goal.
“In the model plant thale cress, we have discovered the signal that activates the female gamete to form a new seed,” says Grossniklaus.
The fertilization process in plants consists of two events. Two sperm cells merge with one female gamete each — one sperm cell fertilizes the egg, from which the embryo and ultimately the next generation is formed, while the other one fuses with the central cell, which develops into a placenta-like tissue that supplies the embryo with nutrients. Together, they develop into mature seeds. For fertilization to be successful, sperm cells and female gametes must be in the same phase of the cell cycle — in other words, they need to be “in sync” with each other.
Scientists already knew that the sperm cells in thale cress (Arabidopsis thaliana) are in the preparatory phase for cell division. Grossniklaus’ team has now shown that the quiescent egg cell is also in this phase.
The central cell, on the other hand, remains stuck in the middle of the preceding phase, in which the genetic material gets duplicated. While sperm and egg cells are in the same cell cycle phase, the central cell must first complete DNA synthesis after fertilization before the first division can begin. This interruption in the cell cycle is caused by a protein in the central cell that is not completely degraded and is thus still present. When the sperm fertilizes this gamete, it introduces the protein cyclin, which then activates the decomposition of the inhibitory protein. Only then can the central cell complete DNA synthesis and move into the next phase of the cell cycle.
“For the first time, we have managed to figure out the molecular mechanism of how the signal is delivered from the sperm to the female gamete in order to shift it out of its quiescent state. It signals to the central cell that fertilization was successful and that cell division can now take place,” says first author Sara Simonini.
Root microbiota of tea plants regulate nitrogen homeostasis and theanine synthesis to influence tea quality
by Wei Xin, Jianming Zhang, Yongdong Yu, Yunhe Tian, Hao Li, Xiaolu Chen, Wei Li, Yanlin Liu, Ting Lu, Biyun He, Yan Xiong, Zhenbiao Yang, Tongda Xu, Wenxin Tang in Current Biology
You’d think the complex flavor in a quality cup of tea would depend mainly on the tea varieties used to make it. But a study shows that the making of a delicious cup of tea depends on another key ingredient: the collection of microbes found on tea roots. By altering that assemblage, the authors showed that they could make good-quality tea even better.
“Significant disparities in microbial communities, particularly nitrogen metabolism-related microorganisms, were identified in the roots of tea plants with varying qualities through microbiomics,” says Tongda Xu of Fujian Agriculture and Forestry University in Fujian, China. “Crucially, through the isolation and assembly of a synthetic microbial community from high-quality tea plant roots, we managed to notably enhance the amino acid content in various tea plant varieties, resulting in an improvement in tea quality.”
China harbors a wealth of genetic resources for growing tea plants. But, the researchers explain, improving the quality of tea through molecular genetic breeding methods is challenging. There’s interest in finding other ways to modify and enhance tea, perhaps including the use of microbial agents.
Earlier studies showed that soil microbes living in plant roots affect the way nutrients are taken up and used within plants. In the new study, the researchers wanted to learn more about how specifically root microbes affect tea quality. They found that the microbes in tea roots affected their uptake of ammonia, which in turn influenced the production of theanine, which is key for determining a tea’s taste. They also saw variations in the microbes colonizing different teas.
By comparing tea varieties with different amounts of theanine, they identified a set of microbes that looked promising for altering nitrogen metabolism and boosting theanine levels. They next constructed a synthetic microbial community, dubbed SynCom, that closely mirrored the one found in association with a high-theanine tea variety called Rougui. When they applied SynCom to tea roots, they found it boosted theanine levels. The microbes also allowed Arabidopsis thaliana, a plant commonly used in basic biological studies, to better tolerate low nitrogen conditions.
“The initial expectation for the synthetic microbial community derived from high-quality tea plant roots was to enhance the quality of low-quality tea plants,” says study co-author Wenxin Tang.
“However, to our astonishment, we discovered that the synthetic microbial community not only enhances the quality of low-quality tea plants but also exerts a significant promoting effect on certain high-quality tea varieties. Furthermore, this effect is particularly pronounced in low-nitrogen soil conditions.”
The findings suggest that synthetically produced microbial communities could improve teas, especially when grown in nitrogen-deficient soil conditions, they say. Because tea trees require lots of nitrogen, the discovery could help to reduce the use of chemical fertilizers while promoting the quality of tea trees. The findings may have important implications for agricultural crops more broadly.
“Based on our current experimental findings, the inclusion of the SynCom21 microbial community has not only improved the absorption of ammonium nitrogen in different tea varieties but also enhanced the uptake of ammonium nitrogen in Arabidopsis thaliana,” Xu says.
“This suggests that the ammonium nitrogen uptake-promoting function of SynCom21 may be applicable to various plants, including other crops.”
For instance, they say, it may allow for growing rice with improved qualities including greater protein content. They now plan to further optimize SynCom and assess its use in field trials. They also hope to learn more about how root microbes affect other secondary metabolites in tea trees.
Gut microbiome responds to alteration in female sex hormone status and exacerbates metabolic dysfunction
by Tzu-Wen L. Cross, Abigayle M. R. Simpson, Ching-Yen Lin, Natasha M. Hottmann, Aadra P. Bhatt, Samuel J. Pellock, Erik R. Nelson, Brett R. Loman, Matthew A. Wallig, Eugenio I. Vivas, Jan Suchodolski, Matthew R. Redinbo, Federico E. Rey, Kelly S. Swanson in Gut Microbes
The gut microbiome interacts with the loss of female sex hormones to exacerbate metabolic disease, including weight gain, fat in the liver and the expression of genes linked with inflammation, researchers found in a new rodent study.
The findings may shed light on why women are at significantly greater risk of metabolic diseases such as obesity and Type 2 diabetes after menopause, when ovarian production of female sex hormones diminishes.
“Collectively, the findings demonstrate that removal of the ovaries and female hormones led to increased permeability and inflammation of the gut and metabolic organs, and the high-fat diet exacerbated these conditions,” said Kelly S. Swanson, the director of the Division of Nutritional Sciences and the Kraft Heinz Endowed Professor in Human Nutrition at the University of Illinois Urbana-Champaign who is a corresponding author of the paper. “The results indicated that the gut microbiome responds to changes in female hormones and worsens metabolic dysfunction.”
“This is the first time it has been shown that the response of microbiome to the loss of ovarian hormone production can increase metabolic dysfunction,” said first author Tzu-Wen L. Cross, a professor ofnutrition science and the director of the Gnotobiotic Animal Facility at Purdue University. Cross was a doctoral student at the U. of I. when she began the research.
“The gut microbiome is sensitive to sex hormone changes and can further impact the risk of disease development.”
Cross said early microbiome research, beginning around 2005, looked at how the microbiome contributes to obesity development, but most of those studies focused on males.
“Metabolic dysfunction that is driven by the loss of ovarian-function in menopausal women — and how much the gut microbiome contributes to that — has not been studied. The etiology is clearly very complex, but those gut-microbiome related factors are certainly components that we speculated play a role,” she said.
The scientists created diet-induced obesity in female mice and simulated the loss of female sex hormones by removing the ovaries in half of the population to examine any metabolic and inflammatory changes, including those to enzymes in the gut. The diets for both groups of mice were identical except for the proportion of fat, which constituted 60% or 10% of calories for those in the high-fat and low-fat groups, respectively. In the second leg of the study, fecal samples were harvested from mice with or without ovaries and implanted in germ-free mice to study the impact on weight gain and metabolic and inflammatory activity in the gut, liver and fat tissue.
“The mice that were recipients of the gut microbiome of ovariectomized mice gained more weight and fat mass, and they had greater expression of genes in the liver associated with inflammation, obesity, Type 2 diabetes, fatty liver disease and atherosclerosis compared with those in the control group,” Swanson said.
In assessing the severity of fatty tissue and triglyceride concentrations in the liver, the scientists found that the triglyceride levels were significantly higher and fatty deposits in the liver and groin were greater in the mice that consumed the high-fat diet compared with all other treatment groups, according to the study.
Those on the high-fat diet and those without ovaries had significantly larger fat cells, which are associated with cell death and the infiltration of macrophages — a type of white blood cell that destroys dead cells and microorganisms and secretes pro-inflammatory proteins. Along with elevated expression of the genes associated with inflammation and macrophage markers, these mice had lower expression of genes that are involved with glucose and lipid metabolism.
In the donor mice without ovaries that consumed the low-fat diet, the scientists found increased levels of beta-glucuronidase, an enzyme produced by the colon and some intestinal bacteria that breaks down and recycles steroidal metabolites such as estrogen and various toxins, including carcinogens.
The scientists also examined the expression of genes coding for tight-junction proteins, which affect cell membranes’ permeability. They found that the mice without ovaries and those fed the high-fat diet had lower levels of these proteins in the liver and colon, which suggested their gut barriers were more permeable, compromised by either their diet or the absence of female hormones.
In the livers of the recipient mice that received transplants from donors without ovaries, the scientists found elevated expression levels of the gene for arginase-1, which plays a critical role in the elimination of nitrogenous waste. High levels of this protein have been associated with cardiovascular problems such as hypertension and atherosclerosis, according to the study.
Xrp1 governs the stress response program to spliceosome dysfunction
by Dimitrije Stanković, Luke S Tain, Mirka Uhlirova in Nucleic Acids Research
A study has identified a protein complex that is activated by defects in the spliceosome, the molecular scissors that process genetic information. Future research could lead to new therapeutic approaches to treat diseases caused by faulty splicing.
The genetic material, in the form of DNA, contains the information that is crucial for the correct functioning of every human and animal cell. From this information repository, RNA, an intermediate between DNA and protein, the functional unit of the cell, is generated.
During this process, the genetic information must be tailored for specific cell functions. Information that is not needed (introns) is cut out of the RNA and the important components for proteins (exons) are preserved. A team of researchers led by Professor Dr Mirka Uhlirova at the University of Cologne’s CECAD Cluster of Excellence in Aging Research has now discovered that if the processing of this information no longer works properly, a protein complex (C/EBP heterodimer) is activated and directs the cell towards a dormant state, known as cellular senescence.
All eukaryotes (i.e. organisms in which DNA is enclosed within the cell nucleus) have a spliceosome. This is a machine that performs ‘splicing’, the removal of introns and linking exons to form messenger RNA (mRNA). Malfunctions in the spliceosome lead to diseases known as spliceosomopathies, which may affect many different tissues, and manifest as retinal degeneration or myelodysplastic syndrome, a group of bone marrow diseases affecting the blood.
In the study, the Uhlirova lab used the model organism Drosophila melanogaster, a fruit fly, to investigate how cells within a developing organism respond to spliceosome malfunction. The scientists used a combination of genomics and functional genetics to determine the role of individual genes and interactions among them.
The study showed that cells suffering from a defective spliceosomal U5 snRNP (U5 small nuclear ribonucleoprotein particle) activate a stress signalling response and cellular behaviours that are characteristic of cellular senescence. The senescence programme changes crucial functions of the cells. It prevents cells from dividing while stimulating their secretion.
Senescence is triggered to preserve cells that are damaged, as their immediate elimination would cause more harm than good. However, senescent cell accumulation can have a negative impact on a tissue as well as the whole organism. Therefore, these cells are ultimately eliminated.
Uhlirova’s team identified the C/EBP-heterodimer protein complex, Xrp1/Irbp18, as the critical driver of the stress response programme caused by faulty splicing. Upregulation of Xrp1/Irbp18 in damaged cells led to increased protein production and induced a senescence-like state.
“Senescence is a double-edged sword,” said Uhlirova. One advantage of senescent cells is that they are not all eliminated by cell death at the same time, thus maintaining the integrity of the tissue. After all, partially intact tissue is better than none at all. However, these cells create problems in the long term, as their accumulation promotes disease and ageing.
“A functioning spliceosome is a basic prerequisite for healthy cells, tissue and the entire organism,” she concluded. “Additional investigation of the stress signalling programme we have identified will be important to further unpack the complex responses triggered by defects in the essential machines controlling gene expression — and how we can influence them.”
In future, the results could contribute to the development of therapeutic approaches to treat diseases that are caused by malfunctions of the spliceosome.
Force transmission by retrograde actin flow-induced dynamic molecular stretching of Talin
by Sawako Yamashiro, David M. Rutkowski, Kelli Ann Lynch, Ying Liu, Dimitrios Vavylonis, Naoki Watanabe in Nature Communications
New results reveal a new mode of force transmission in which dynamic molecular stretching bridges the extracellular matrix and flowing F-actin moving at different speeds. This discovery underscores the necessity of molecular elasticity and random coupling for sufficiently transmitting force. The findings also call for revising the role of molecular unfolding.
Cell biology has possibly never jumped to the next level in the same way. In multicellular organisms, cell migration and mechanosensing are essential for cellular development and maintenance. These processes rely on talin, the key focal adhesion — or FA — protein, central in connecting adjacent cellular matrices and enabling force transmission between them.
Talins are commonly considered fully extended at FAs between actin filaments — or F-actin — and the anchor-like integrin receptor. Yet, a research team led by Kyoto University have previously observed that the actin network constantly moves over FAs as a single unit: a unique phenomenon contradicting prevailing notions.
“This begs the question: how does talin manage to simultaneously maintain the intercellular connection while transmitting force?” asks corresponding author Sawako Yamashiro at KyotoU’s Graduate School of Life Sciences.
Most significantly, the team’s results reveal a new mode of force transmission in which dynamic molecular stretching bridges the extracellular matrix and flowing F-actin moving at different speeds. This discovery underscores the necessity of molecular elasticity and random coupling for sufficiently transmitting force.
“On a human scale, this phenomenon can be visualized as a super flexible anime character. He is gripping onto a train passing at around 50 km/h,” illustrates Yamashiro. The train represents the flowing F-actin, while a station platform is the substrate.
The superhero plays the talin FA protein that would either be carried away unstretched or remain on the substrate.
“Occasionally, however, when both ends of talin are firmly anchored, it gets stretched by the pull because some parts of this protein can unfold like a spring,” explains Yamashiro.
Aided by intracellular fluorescent talin single-molecule imaging, Yamashiro’s team observed and calculated that approximately 4% of the talin links the F-actin and the substrate via an elastic transient clutch. In contrast, the remaining majority are bound to either end. These findings also call for revising the role of molecular unfolding, updating the traditional view that it functions as a mechanosensor and a shock absorber when molecules unfold under external force.
“However, our results suggest that molecular unfolding facilitates the transmission of force rather than absorbing it,” says coauthor Dimitrios Vavylonis at Lehigh University.
“We can expect further use of intracellular single-molecule microscopy to witness other possible intra- and extra-cellular superheroic behaviours, such as talin’s elastic transient clutch,” concludes coauthor Naoki Watanabe, also at KyotoU’s Graduate School of Life Sciences.
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