I’m sure you can all relate, you go to fix the sink and in the process you build a new kitchen on accident. Anyone… no? Well that is sort of what happened to researchers recently, while developing a new cancer drug, they discovered that mice lacking a specific protein live longer lives with fewer age-related illnesses. The mice, which were bred to lack the TRAP-1 protein, demonstrated less age related tissue degeneration, obesity, and spontaneous tumor formation when compared to normal mice. Pretty awesome if you think about the fact that the findings could change how scientists view the metabolic networks within cells.
In healthy cells, TRAP-1 is an important regulator of metabolism and has been shown to regulate energy production in mitochondria [the cell organelles that generate chemically useful energy for the cell, basically the powerhouse of the cell as most know it by]. However, in the mitochondria of cancer cells, TRAP-1 is universally overproduced.
The teams report shows how the “knockout†mice bred to lack the TRAP-1 protein compensate for this loss by switching to alternative cellular mechanisms for making energy.
[Loony Hint: In case it isn’t clear, knockout mice are bred to lack a specific gene, they do this either by breeding or, depending on the complexity, by replacing it or disrupting it with an artificial piece of DNA]
“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,†said Dario C. Altieri. M.D., Robert and Penny Fox Distinguished Professor and director of The Wistar Institute’s National Cancer Institute-designated Cancer Center. “Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells.â€
“We usually link the reprogramming of metabolic pathways with human diseases, such as cancer,†Altieri said. “What we didn’t expect to see were healthier mice with fewer tumors.â€
The researchers created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, Gamitrinib, which targets the protein in the mitochondria of tumor cells. For those who love proteins, TRAP-1 is a member of the heat shock 90 [HSP90] protein family [for those who didn’t click the link HSP90 proteins are “chaperone” proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria]. Tumors use HSP90 proteins, like TRAP-1, to help survive therapeutic attack.
“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in in death of the tumor cells,†Altieri said. “Mice that lack TRAP-1 from the start, however, have three weeks in the womb to compensate for the loss of the protein.â€
The researchers found that in their knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which then triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This causes mitochondria in knockout mice to produce deregulated levels of ATP, the chemical used as an energy source to power all the everyday molecular reactions that allow a cell to function.
This increased mitochondrial activity actually creates a moderate boost in oxidative stress [or that crazy “free radical damage”] and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation—slowing growth down to allow the cell’s natural repair mechanisms to take effect. Which further supports the antioxidant news that came out recently
According to the team, their observations provide a mechanistic foundation for the role of chaperone molecules, like HSP90, in the regulation of bioenergetics in mitochondria — which is just how cells produce and use the chemical energy they need to survive and grow. Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and dramatically show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.
“Our findings strengthen the case for targeting HSP90 in tumor cells, but it also opens up a fascinating array of questions that may have implications for metabolism and longevity,†Altieri said. “I predict that the TRAP-1 knockout mice will be a valuable tool for answering these questions.â€
It’s a shame everything doesn’t end that well. But this might open up new ways to fight obesity and to live longer in general. Hopefully we can see some further studies done sometime soon!
Want more? You can find the full study –here!
Sources:Â
Lisanti, S., Tavecchio, M., Chae, Y., Liu, Q., Brice, A., Thakur, M., Languino, L., Altieri, D. (2014). Deletion of the Mitochondrial Chaperone TRAP-1Â Uncovers Global Reprogramming of Metabolic Networks Cell Reports DOI: 10.1016/j.celrep.2014.06.061