The mice lacking specific protein live longer lives with less disease related to age -
While developing a new drug against cancer, researchers the Wistar Institute have discovered that mice lacking a particular protein are living longer lives with less age-related diseases. Mice that lack the TRAP-1 protein, showed less degeneration age-related tissue, obesity and the formation of spontaneous tumors compared to normal mice. Their findings could change the way scientists consider the metabolic networks in cells.
In healthy cells, TRAP-1 is an important regulator of the metabolism and has been shown to regulate the production of energy in the mitochondria, organelles that chemically produce useful energy for the cell. In the mitochondria of cancer cells, TRAP-1 is universally surplus.
The report of the Wistar team, which appears in the journal Cell Reports (available online), shows how mice "knockout" high to lack the protein Trappist 1 offset this loss by switching to alternative mechanisms for cellular energy.
"We see this amazing change in TRAP-1 knockout mice, they showed fewer signs of aging and are less likely to develop cancer," said Dario C. Altieri. MD, and Robert Penny Fox Distinguished Professor and Director of the Centre National cancer Institute designated cancer of the Wistar Institute. "our findings provide unexpected explanation of how TRAP-1 and related proteins regulate metabolism within our cells."
"We usually are connecting the reprogramming of metabolic pathways with human diseases such as cancer," said Altieri. "what we did not expect to see mice were healthier with fewer tumors."
Altieri and colleagues created knockout mice TRAP-1 as part of their ongoing investigation into their new drug, Gamitrinib, designed the proteins in the mitochondria of tumor cells. TRAP-1 is a member of the heat shock 0 (HSP0) family of proteins, which are "chaperone" proteins that guide the physical formation of other proteins and serve a regulatory function in mitochondria. Tumors using HSP0 protein, as TRAP-1, to help survive the therapeutic attack.
"In tumors, the TRAP-1 loss is devastating, triggering a series of catastrophic defects, including metabolic problems that result ultimately in the death of tumor cells," said Altieri. "The mice lacking TRAP-1 from the beginning, however, have three weeks in the womb for the loss of the protein."
The researchers found that, in their knockout mouse, 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 a source of energy to power all molecular reactions everyday that allow a cell to function.
This increased mitochondrial activity actually creates a moderate boost oxidative stress ( "free radical damage") and damage of the associated DNA. Although DNA damage may seem cons-productive for longevity and good health, low levels of DNA damage effectively reduces the growth of cell proliferation slows down to allow natural repair mechanisms of the cell to take effect.
According to Altieri, their findings provide a mechanistic foundation for the role of chaperone molecules, such as HSP0 in regulating mitochondrial bioenergetics in cells how to produce and use chemical energy they need to survive and grow. their results explain some conflicting results in the literature concerning the regulation of bioenergetic and dramatically show how compensation mechanisms can occur when these molecules chaperones are taken out of the equation.
"Our results strengthen the case for targeting HSP0 in tumor cells, but it also opens up a fascinating range of issues that can affect the metabolism and longevity," said Altieri. "I predict that the knockout mice TRAP-1 will be a valuable tool for answering these questions."
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