Scientists solve a 100-year-old mystery about cancer
The year 2021 marks the 100th anniversary of a fundamental discovery that's taught in every biochemistry textbook. In 1921, German physician Otto Warburg observed that cancer cells harvest energy from glucose sugar in a strangely inefficient manner: rather than "burn" it using oxygen, cancer cells do what yeast do -- they ferment it. This oxygen-independent process occurs quickly, but leaves much of the energy in glucose untapped.
Various hypotheses to explain the Warburg effect have been proposed over the years, including the idea that cancer cells have defective mitochondria -- their "energy factories" -- and therefore cannot perform the controlled burning of glucose. But none of these explanations has withstood the test of time. (Cancer cells' mitochondria work just fine, for example.)
Now a research team at the Sloan Kettering Institute led by immunologist Ming Li offers a new answer, based on a hefty set of genetic and biochemical experiments and published January 21 in the journal Science.
It comes down to a previously unappreciated link between Warburg metabolism and the activity of a powerhouse enzyme in the cell called PI3 kinase.
"PI3 kinase is a key signaling molecule that functions almost like a commander-in-chief of cell metabolism," Dr. Li says. "Most of the energy-costly cellular events in cells, including cell division, occur only when PI3 kinase gives the cue."
As cells shift to Warburg metabolism, the activity of PI3 kinase is increased, and in turn, the cells' commitment to divide is strengthened. It's a bit like giving the commander-in-chief a megaphone.
The findings revise the commonly accepted view among biochemists that sees metabolism as secondary to cell signaling. They also suggest that targeting metabolism could be an effective way to thwart cancer growth.
Challenging the Textbook View
Dr. Li and his team, including graduate student Ke Xu, studied Warburg metabolism in immune cells, which also rely on this seemingly inefficient form of metabolism. When immune cells are alerted to the presence of an infection, a certain type called T cells shift from the typical oxygen-burning form of metabolism to Warburg metabolism as they grow in number and ramp up infection-fighting machinery.
The key switch that controls this shift is an enzyme called lactate dehydrogenase A (LDHA), which is made in response to PI3 kinase signaling. As a result of this switch, glucose remains only partially broken down and the cell's energy currency, called ATP, is quickly generated in the cell's cytosol. (In contrast, when cells use oxygen to burn glucose, the partially broken down molecules travel to the mitochondria and are further broken down there to make ATP on a delay.)
Dr. Li and his team found that in mice, T cells lacking LDHA could not sustain their PI3 kinase activity, and as a result could not effectively fight infections. To Dr. Li and his team, this implied that this metabolic enzyme was controlling a cell's signaling activity.
"The field has worked under the assumption that metabolism is secondary to growth factor signaling," Dr. Li says. "In other words, growth factor signaling drives metabolism, and metabolism supports cell growth and proliferation. So the observation that a metabolic enzyme like LDHA could impact growth factor signaling through PI3 kinase really caught our attention."
Like other kinases, PI3 kinase relies on ATP to do its work. Since ATP is the net product of Warburg metabolism, a positive feedback loop is set up between Warburg metabolism and PI3 kinase activity, securing PI3 kinase's continued activity -- and therefore cell division.
As for why activated immune cells would preferentially resort to this form of metabolism, Dr. Li suspects it has to do with the cells' need to produce ATP quickly to ramp up their cell division and infection-fighting machinery. The positive feedback loop ensures that once this program is engaged, it will be sustained until the infection is eradicated.
The Cancer Connection
Though the team made their discoveries in immune cells, there are clear parallels to cancer.
"PI3 kinase is a very, very critical kinase in the context of cancer," Dr. Li says. "It's what sends the growth signal for cancer cells to divide, and is one of the most overly active signaling pathways in cancer."
As with immune cells, cancer cells may employ Warburg metabolism as a way to sustain the activity of this signaling pathway and therefore ensure their continued growth and division. The results raise the intriguing possibility that doctors could curb cancer growth by blocking the activity of LDHA -- the Warburg "switch."
News source: www.sciencedaily.com
Article: Ke Xu, Na Yin, Min Peng, Efstathios G. Stamatiades, Amy Shyu, Peng Li, Xian Zhang, Mytrang H. Do, Zhaoquan Wang, Kristelle J. Capistrano, Chun Chou, Andrew G. Levine, Alexander Y. Rudensky, Ming O. Li. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity. Science, 2021; 371 (6527): 405 DOI: 10.1126/science.abb2683
New possibilities to prevent sudden cardiac death
Nearly a half-million people a year die from sudden cardiac death (SCD) in the U.S. -- the result of malfunctions in the heart's electrical system.
A leading cause of SCD in young athletes is arrhythmogenic cardiomyopathy (ACM), a genetic disease in which healthy heart muscle is replaced over time by scar tissue (fibrosis) and fat.
Stephen Chelko, an assistant professor of biomedical sciences at the Florida State University College of Medicine, has developed a better understanding of the pathological characteristics behind the disease, as well as promising avenues for prevention. His findings are published in the current issue of Science Translational Medicine.
Individuals with ACM possess a mutation causing arrhythmias, which ordinarily are non-fatal if managed and treated properly. However, Chelko shows that exercise not only amplifies those arrhythmias, but causes extensive cell death. Their only option is to avoid taking part in what should be a healthy and worthwhile endeavor: exercise.
"There is some awful irony in that exercise, a known health benefit for the heart, leads to cell death in ACM subjects," Chelko said. "Now, we know that endurance exercise, in particular, leads to large-scale myocyte cell death due to mitochondrial dysfunction in those who suffer from this inherited heart disease."
Several thousand mitochondria are in nearly every cell in the body, processing oxygen and converting food into energy. Considered the powerhouse of all cells (they produce 90 percent of the energy our bodies need to function properly), they also play another important role as a protective antioxidant.
As mitochondria fail to function properly, and myocyte cells in the heart die, healthy muscles are replaced by scar tissue and fatty cells. Eventually, the heart's normal electrical signals are reduced to an erratic and disorganized firing of impulses from the lower chambers, leading to an inability to properly pump blood during heavy exercise. Without immediate medical treatment, death occurs within minutes.
Chelko's research gets to the heart of the process involved in mitochondrial dysfunction.
"Ultimately, mitochondria become overwhelmed and expel 'death signals' that are sent to the nucleus, initiating large-scale DNA fragmentation and cell death," Chelko said. "This novel study unravels a pathogenic role for exercise-induced, mitochondrial-mediated cell death in ACM hearts."
In addition to providing a better understanding of the process involved, Chelko discovered that cell death can be prevented by inhibiting two different mitochondrial proteins. One such approach utilizes a novel targeting peptide developed for Chelko's research by the National Research Council in Padova, Italy.
That discovery opens avenues for the development of new therapeutic options to prevent myocyte cell death, cardiac dysfunction and the pathological progression leading to deadly consequences for people living with ACM.
This research was funded by an American Heart Association Career Development Award.
News source: www.sciencedaily.com
Mitochondrial function can play significant part in serious disease
Disorders of the cells' energy supply can cause a number of serious diseases, but also seem to be connected to ageing. More research is needed on mitochondrial function to find future treatments. A new study involving researchers at Karolinska Institutet shows how an important molecule inside the mitochondria affects their function in mice and fruit flies. The study, which is published in Science Advances, adds valuable knowledge on formerly relatively unexplored protein modifications.
In each cell of the body is an organ called the mitochondrion, which converts nutrients in our food to energy. Mitochondria are an essential part of the metabolism, and when things go wrong we can develop serious diseases.
Mitochondrial dysfunction is the hallmark of a group of rare genetic disorders but can also be observed in common diseases such as diabetes, heart disease, neurodegenerative diseases and the normal ageing process.
More research is needed on mitochondria and how they communicate with the rest of the cell if scientists are to find new therapeutic approaches to improve mitochondrial function.
Researchers at Karolinska Institutet, the Max-Planck Institute for Biology of Ageing in Cologne and the University of California San Diego have now studied how the methylation of proteins affects different mitochondrial processes.
Methylation is a chemical modification in which a methyl group (CH3) is added to a molecule, thereby potentially affecting its function. S-Adenosylmethionine (SAM), also known as AdoMet, is the main methyl group donor within the cell, including inside of mitochondria.
"We're interested in studying this particular molecule since the production of SAM changes in cancer and when we age," says Anna Wredenberg, researcher at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
By completely removing SAM from the mitochondria of fruit flies and mice, the researchers have been able to study which processes in the mitochondria are dependent on methylation.
"Earlier studies have shown that both SAM and cellular energy levels drop during ageing. Our study suggests a link between these two pathways by demonstrating that low SAM levels can influence mitochondrial energy production."
The study has identified which of the mitochondrial proteins are methylated and how methylation affects them, and how these modifications might affect mitochondrial function. The researchers also demonstrate the physiological consequences of the lack of such changes. However, several questions still need answering.
"Our study has provided an indication that some modifications can be modulated by diet, but we need to continue examining if we can change the pathological process for the better," says Anna Wredenberg. "So far we've only looked at protein changes, but other molecules can also be modified by intra-mitochondrial SAM. We have to study these modifications to get a better understanding of the role it plays."
The study was financed by the Swedish Research Council, the European Research Council, the Knut and Alice Wallenberg Foundation, the Max Planck Society and the Ragnar Söderberg Foundation. There are no reported conflicts of interest.
News Source: https://www.sciencedaily.com/releases/2021/02/210219155928.htm
Florian A. Schober, David Moore, Ilian Atanassov, Marco F. Moedas, Paula Clemente, Ákos Végvári, Najla El Fissi, Roberta Filograna, Anna-Lena Bucher, Yvonne Hinze, Matthew The, Erik Hedman, Ekaterina Chernogubova, Arjana Begzati, Rolf Wibom, Mohit Jain, Roland Nilsson, Lukas Käll, Anna Wedell, Christoph Freyer, Anna Wredenberg. The one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters. Science Advances, 2021; 7 (8): eabf0717 DOI: 10.1126/sciadv.abf0717
New way to halt excessive inflammation
RCSI researchers have discovered a new way to 'put the brakes' on excessive inflammation by regulating a type of white blood cell that is critical for our immune system.
The discovery has the potential to protect the body from unchecked damage caused by inflammatory diseases.
The paper, led by researchers at RCSI University of Medicine and Health Sciences, is published in Nature Communications.
When immune cells (white blood cells) in our body called macrophages are exposed to potent infectious agents, powerful inflammatory proteins known as cytokines are produced to fight the invading infection. However, if these cytokine levels get out of control, significant tissue damage can occur.
The researchers have found that a protein called Arginase-2 works through the energy source of macrophage cells, known as mitochondria, to limit inflammation. Specifically they have shown for the first time that Arginase-2 is critical for decreasing a potent inflammatory cytokine called IL-1.
This discovery could allow researchers to develop new treatments that target the Arginase-2 protein and protect the body from unchecked damage caused by inflammatory diseases.
"Excessive inflammation is a prominent feature of many diseases such as multiple sclerosis, arthritis and inflammatory bowel diseases. Through our discovery, we may be able to develop novel therapeutics for the treatment of inflammatory disease and ultimately improve the quality of life for people with these conditions," commented senior author on the paper Dr Claire McCoy, Senior Lecturer in Immunology at RCSI.
The study was led by researchers at the School of Pharmacy and Biomolecular Sciences, RCSI (Dr Claire McCoy, Dr Jennifer Dowling and Ms Remsha Afzal) in collaboration with a network of international researchers from Australia, Germany, and Switzerland.
The research was funded by Science Foundation Ireland, with initial stages of the research originating from a grant from the National Health Medical Research Council, Australia.
News source: www.sciencedaily.com
Dowling, J.K., Afzal, R., Gearing, L.J. et al. Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages. Nat Commun 12, 1460 (2021). https://doi.org/10.1038/s41467-021-21617-2
Mitochondrial dysfunction caused by bacteria activates intrinsic apoptosis and inflammation
Monash Biomedicine Discovery Institute (BDI) scientists have discovered a previously unknown method used by bacteria to evade immune responses.
The study, published in Nature Microbiology, points to potential new ways of countering bacterial infections, which are becoming increasingly resistant to antibiotics.First author Dr Pankaj Deo said researchers in Dr Thomas Naderer’s laboratory took a different approach to understanding the process by which bacteria release toxins that disarm the “powerhouse” mitochondria in immune cells.The study showed that immune cells sense that their mitochondria are no longer functional during infections, which triggers apoptosis. “Ironically, it is the activation of host cell death factors that deliver the final blow to mitochondria which induces apoptosis, not the bacterial toxins themselves,” Dr Pankaj said.The researchers genetically targeted apoptotic factors and showed that they were able to reduce inflammation in mice, which increased health outcomes.They used the bacterial pathogens Neisseria gonorrhoeae, uropathogenic Escherichia coli and the deadly Pseudomonas aeruginosa, prevalent in hospitals and which can be multi-drug resistant. However, the findings would apply to other species of bacteria too, Dr Deo said.Dr Naderer, who oversaw the research, said that understanding the ways some bacterial infections evade immune response by targeting mitochondria opens new therapeutic possibilities.“There’s been a lot of effort trying to block endotoxins that kill immune cells but this study really shifts the focus onto different toxins that might be more important,” Dr Naderer said.“It gives us a few good leads that we can look at as a next step,” he said.“We’ve shown in this paper that we can accelerate the immune response,” he said. “The other side is that if that response persists and we get constant inflammation – which is usually associated with bacterial infection and which causes a lot of tissue damage – we have a new way to shut down that tissue-damaging inflammation.”“What scientists have thought before is that when endotoxins are released by bacteria they induce an inflammatory type of programmed cell death called pyroptosis in immune cells,” Dr Deo said. Endotoxins are part of the external cell wall of essentially all Gram-negative bacteria.“We’ve found that the pathogenic bacteria use a similar mechanism to release additional toxins,” he said. “They kill immune cells by releasing small surface structures called outer membrane vesicles – packages of toxins that target mitochondria. The mitochondria are disarmed, become dysfunctional then die according to apoptosis or cellular suicide.”The scientists will investigate drugs that are now advancing to the clinic, and at repurposing drugs already in use, perhaps as anti-cancer treatments, to see if they can be used to clear bacterial infections.
News source: www.technologynetworks.com
Article: Deo et al. (2020). Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation. Nature Microbiology. DOI: https://doi.org/10.1038/s41564-020-0773-2
