Excessive antioxidant use may interfere with cell stress response, study finds

By Will Chu

- Last updated on GMT

"Consuming large doses of antioxidants is probably not the best idea, as you're also potentially interfering with normal ROS signals that are helpful and important." ©iStock/Zardinax
"Consuming large doses of antioxidants is probably not the best idea, as you're also potentially interfering with normal ROS signals that are helpful and important." ©iStock/Zardinax

Related tags: Oxygen

Antioxidants’ effects may not be altogether beneficial as a study shows the reactive oxygen species (ROS) molecule that antioxidants are so efficient at eliminating may aid in maintaining health. 

The main finding focuses on a protein called IRE-1, which is located on the outside of the endoplasmic reticulum (ER), a cell structure that makes proteins like insulin.

IRE-1 monitors the ER, flagging up any abnormal proteins that are created and alerting the cell to apply corrective measures or create a new protein.

Researchers found that IRE-1 also reacted to ROS molecules, setting in motion an antioxidant response that increases the cell's resistance to stress.

The findings may well provide a note of caution to those who consume excessive amounts of antioxidant supplements with a view to protecting themselves against damage from ROS.

"In clinical trials, therapies with antioxidants have been pretty much a bust, and it's not entirely clear why,"​ said Dr Keith Blackwell, associate research director and co-head of the Section on Islet Cell and Regenerative Biology at Joslin Diabetes Center and Professor of Genetics at Harvard Medical School.

"But blindly consuming large doses of antioxidants is probably not the best idea, because while your intent would be to protect yourself from damage, you're also potentially interfering with normal ROS signals that are helpful and important."

Blackwell does not dispute that at elevated levels, ROS molecules can cause protein impairment, accelerated aging and disease progression.

ROS – a normal cell response?

sport supplements
While supplement use has been shown to be beneficial, an excess is not recommended. ©iStock

"But over the past several years, there's been a growing body of evidence that there are also ROS molecules that appear to be physiologically normal and act as normal cell signals," he added.

As an example, ROS molecules can be generated that inhibit the enzyme phosphatase​ and increase the effect of kinase activity​.

The study began by using the simple nematode C. elegans​ progressing onto human cells, where the IRE-1 molecular pathway works in a very similar way.

Detection of the ROS molecule was achieved via a ROS-sensitive fluorescent probe with ROS levels recorded that were relative to total protein concentration.

"On one hand, IRE-1 senses misfolded proteins inside the ER, and it turns on a corrective mechanism called the unfolded protein response (UPR),”​ said Blackwell.

“On the other hand, when IRE-1 gets a signal from ROS molecules outside the ER, it shuts off the unfolded protein response and turns on an antioxidant response,”​ he added.

Unexpectedly Blackwell’s team also discovered that this functional switch is controlled by a single oxygen molecule, which attaches to a single amino acid at a specific place in IRE-1, significantly altering its structure and function.

IRE1 mechanism of action

insulin cell
The endoplasmic reticulum (ER) is a cell structure that makes proteins like insulin. ©iStock

The role of IRE-1 function in response to abnormal proteins in the ER has long been established​. ​This latest study serves to detail another function in which its cytoplasmic enzyme appears to convert and interpret ROS signals from the ER.

The researchers suggested IRE-1’s role uses a molecular ‘switch’ in which an amino acid cysteine (cys), present within the pathway, undergoes a chemical change as a result of the ROS signal.

The change is an addition of a single oxygen atom. This, said the team, appeared to inhibit the IRE-1 kinase enzyme and promote recruitment and activation of p38 signaling at IRE-1.

The p38 signalling pathway serves as a gateway to convert signals and play a major role in numerous biological processes including inflammation, cell cycle, cell death, and cell differentiation in specific cell types.

“Our data provide a striking example of a well-described protein having an unexpected function and suggest that Cys-based signaling can regulate proteins in diverse ways,”​ the study concluded.

Source: Molecular Cell

Published online ahead of print, DOI: http://dx.doi.org/10.1016/j.molcel.2016.07.019

“Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response.”

Authors: John Hourihan et al.

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