New cause of cell aging discovered
New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works. The findings potentially pave the way for better cancer treatments and revolutionary new drugs that could vastly improve human health in the twilight years.
The work, from Assistant Professor of Chemical Engineering and Materials Science Nick Graham and his team in collaboration with Scott Fraser, Provost Professor of Biological Sciences and Biomedical Engineering, and Pin Wang, Zohrab A. Kaprielian Fellow in Engineering, was recently published in the Journal of Biological Chemistry.
"To drink from the fountain of youth, you have to figure out where the fountain of youth is, and understand what the fountain of youth is doing," Graham said. "We're doing the opposite; we're trying to study the reasons cells age, so that we might be able to design treatments for better aging."
What causes cells to age?
To achieve this, lead author Alireza Delfarah, a graduate student in the Graham lab, focused on senescence, a natural process in which cells permanently stop creating new cells. This process is one of the key causes of age-related decline, manifesting in diseases such as arthritis, osteoporosis and heart disease.
"Senescent cells are effectively the opposite of stem cells, which have an unlimited potential for self-renewal or division," Delfarah said. "Senescent cells can never divide again. It's an irreversible state of cell cycle arrest."
The research team discovered that the aging, senescent cells stopped producing a class of chemicals called nucleotides, which are the building blocks of DNA. When they took young cells and forced them to stop producing nucleotides, they became senescent, or aged.
"This means that the production of nucleotides is essential to keep cells young," Delfarah said. "It also means that if we could prevent cells from losing nucleotide synthesis, the cells might age more slowly."
Graham's team examined young cells that were proliferating robustly and fed them molecules labeled with stable isotopes of carbon, in order to trace how the nutrients consumed by a cell were processed into different biochemical pathways.
Scott Fraser and his lab worked with the research team to develop 3D imagery of the results. The images unexpectedly revealed that senescent cells often have two nuclei, and that they do not synthesize DNA.
Before now, senescence has primarily been studied in cells known as fibroblasts, the most common cells that comprised the connective tissue in animals. Graham's team is instead focusing on how senescence occurs in epithelial cells, the cells that line the surfaces of the organs and structures in the body and the type of cells in which most cancers arise.
Graham said that senescence is most widely known as the body's protective barrier against cancer: When cells sustain damage that could be at risk of developing into cancer, they enter into senescence and stop proliferating so that the cancer does not develop and spread.
"Sometimes people talk about senescence as a double-edged sword, that it protects against cancer, and that's a good thing," Graham said. "But then it also promotes aging and diseases like diabetes, cardiac dysfunction or atherosclerosis and general tissue dysfunction," he said.
Graham said the goal was not to completely prevent senescence, because that might unleash cancer cells.
"But then on the other hand, we would like to find a way to remove senescent cells to promote healthy aging and better function," he said.
Graham said that the team's research has applications in the emerging field of senolytics, the development of drugs that may be able to eliminate aging cells. He said that human clinical trials are still in early stages, but studies with mice have shown that by eliminating senescent cells, mice age better, with a more productive life span.
"They can take a mouse that's aging and diminishing in function, treat it with senolytic drugs to eliminate the senescent cells, and the mouse is rejuvenated. If anything, it's these senolytic drugs that are the fountain of youth," Graham said.
He added that in order for successful senolytic drugs to be designed, it was important to identify what is unique about senescent cells, so that drugs won't affect the normal, non-senescent cells.
"That's where we're coming in -- studying senescent cell metabolism and trying to figure out how the senescent cells are unique, so that you could design targeted therapeutics around these metabolic pathways," Graham said.
News Source : www.sciencedaily.com
Journal Reference:
Alireza Delfarah, Sydney Parrish, Jason A. Junge, Jesse Yang, Frances Seo, Si Li, John Mac, Pin Wang, Scott E. Fraser, Nicholas A. Graham. Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells. Journal of Biological Chemistry, 2019; 294 (27): 10564 DOI: 10.1074/jbc.RA118.005806
Broken mitochondria use 'eat me' proteins to summon their executioners
When mitochondria become damaged, they avoid causing further problems by signaling cellular proteins to degrade them. In a paper publishing April 11, 2019, in the journal Developmental Cell, scientists in Norway report that they have discovered how the cells trigger this process, which is called mitophagy. In cells with broken mitochondria, two proteins -- NIPSNAP 1 and NIPSNAP 2 -- accumulate on the mitochondrial surface, functioning as "eat me" signals, recruiting the cellular machinery that will destroy them.
NIPSNAP 1 and 2 are normally found inside healthy mitochondria, although their function inside the cell is unknown. "When a cell's respiration chain is disrupted, and the mitochondria are damaged, import of these proteins into the matrix and inner membrane space of the mitochondria is interrupted," says senior author Anne Simonsen, a professor at the Department of Molecular Medicine at the Institute of Basic Medical Sciences of the University of Oslo. "In that case, the import system does not function and they remain bound to the surface of the damaged mitochondria signaling for mitophagy."
In this study, the researchers studied human HeLa cells where both NIPSNAP1 and NIPSNAP 2 function were eliminated. "When we do that, these cells cannot clear the mitochondria after damage," says Simonsen. However, in cells with functional NIPSNAP proteins, when mitophagy was induced through the addition of a chemical disruptor, they observed that the NIPSNAP proteins act in concert with the PINK and PARKIN proteins, proteins already known to have a role in triggering autophagy and to have a role in Parkinson's Disease.
PARKIN labels cells with ubiquitin, a small protein that directs the cells towards degradation. "Ubiquitin is the classical signal to recruit autophagy," says co-author Terje Johansen, of the University of Tromsø -- The Arctic University of Norway. "What we saw is that in addition to ubiquitin, NIPSNAP proteins are required to recruit autophagy proteins; they are not targeted to the mitochondria unless these NIPSNAP proteins are found on the surface."
The team showed this finding has important physiological implications in vivo by investigating the NIPSNAP/PINK/PARKIN mechanism in a zebrafish animal model. They compared wild-type zebrafish and a fish line with reduced NIPSNAP1 protein abundance.
"We see that the mutant fish lacking adequate functional NIPSNAP1 are not able to move as the wild-type fish," says Simonsen. They have a Parkinsonian-like phenotype with reduced numbers of dopaminergic neurons. However, they could rescue this locomotion defect by adding L-dopa, the same compound used to treat human Parkinson's Disease, to the water.
Even more dramatically, animals entirely lacking NIPSNAP1 protein died within five days. "Clearly, clearance of mitochondria is important for the health of these dopaminergic neurons. That is particularly important since neurons generally cannot divide," says Johansen.
As evolutionarily conserved proteins, NIPSNAP proteins are found throughout the animal kingdom, including humans.
This work was partly funded by the Research Council of Norway, the Norwegian Cancer Society, and the Parkinson's Disease Foundation.
News Source : www.sciencedaily.com
Journal Reference:
Yakubu Princely Abudu, Serhiy Pankiv, Benan John Mathai, Alf Håkon Lystad, Christian Bindesbøll, Hanne Britt Brenne, Matthew Yoke Wui Ng, Bernd Thiede, Ai Yamamoto, Thaddaeus Mutugi Nthiga, Trond Lamark, Camila V. Esguerra, Terje Johansen, Anne Simonsen. NIPSNAP1 and NIPSNAP2 Act as 'Eat Me' Signals for Mitophagy. Developmental Cell, 2019; DOI: 10.1016/j.devcel.2019.03.013
Caffeine from four cups of coffee protects the heart with the help of mitochondria
A new study shows that a caffeine concentration equivalent to four cups of coffee promotes the movement of a regulatory protein into mitochondria, enhancing their function and protecting cardiovascular cells from damage.
Caffeine consumption has been associated with lower risks for multiple diseases, including type II diabetes, heart disease, and stroke, but the mechanism underlying these protective effects has been unclear. A new study now shows that caffeine promotes the movement of a regulatory protein into mitochondria, enhancing their function and protecting cardiovascular cells from damage. The work, publishing 21 June in the open access journal PLOS Biology, by Judith Haendeler and Joachim Altschmied of the Medical Faculty, Heinrich-Heine-University and the IUF-Leibniz Research Institute for Environmental Medicine in Duesseldorf, Germany, and colleagues, found that the protective effect was reached at a concentration equivalent to consumption of four cups of coffee, suggesting the effect may be physiologically relevant.
News source: https://www.sciencedaily.com/releases/2018/06/180621141008.htm
PLOS. "Caffeine from four cups of coffee protects the heart with the help of mitochondria." ScienceDaily. ScienceDaily, 21 June 2018. <www.sciencedaily.com/releases/2018/06/180621141008.htm>.
Researchers can finally modify plant mitochondrial DNA
Rice in field (stock image). Credit: © orijinal_x / Adobe Stock
Researchers have edited plant mitochondrial DNA for the first time, which could lead to a more secure food supply. Nuclear DNA was first edited in the early 1970s, chloroplast DNA was first edited in 1988, and animal mitochondrial DNA was edited in 2008. However, no tool previously successfully edited plant mitochondrial DNA. Researchers used their technique to create four new lines of rice and three new lines of rapeseed (canola).
Nuclear DNA was first edited in the early 1970s, chloroplast DNA was first edited in 1988, and animal mitochondrial DNA was edited in 2008. However, no tool previously successfully edited plant mitochondrial DNA.
Researchers used their technique to create four new lines of rice and three new lines of rapeseed (canola).
"We knew we were successful when we saw that the rice plant was more polite -- it had a deep bow," said Associate Professor Shin-ichi Arimura, joking about how a fertile rice plant bends under the weight of heavy seeds.
Arimura is an expert in plant molecular genetics at the University of Tokyo and led the research team, whose results were published in Nature Plants. Collaborators at Tohoku University and Tamagawa University also contributed to the research.
News source: www.sciencedaily.com
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10th Anniversary of Targeting Mitochondria Congress The World Mitochondria Society has the pleasure to announce the 10th Anniversary of Targeting Mitochondria Congress, which will be held in Berlin, Germany, on October 27th – 29th, 2019. To know more about the Congress, please visit the Home page here |
Program of Targeting Mitochondria 2019 Congress/Speakers/Early Registration/May 21, 2019
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