New Delhi: Researchers have found that excess iron in neurons could lower the brain cells’ defences, increasing vulnerability to stressors and other cellular insults through a process they named ‘chronoferroptosis’.
Findings published in the journal Cell Death Discovery point to iron accumulation in brain cells as a key target in the effort to predict, prevent, and treat neurodegenerative diseases, researchers said.
“Resilience has become a huge topic of discussion when it comes to Alzheimer’s disease and other neurodegenerative disorders, trying to make the brain more resilient in the face of stressors that contribute to neurodegeneration,” senior author Pam Maher, a research professor at Salk Institute for Biological Studies, US, said.
“Our study reveals that cells lose resilience when iron hits a certain level, making neurons more susceptible to stressors that damage or even kill them,” Maher said.
Researchers said previous studies have found that iron can slowly build up inside neurons.
While early in life, the accumulation of iron appears to have little effect on neuron function, later in life, it can contribute to a slow neuronal demise, they said.
The team studied nerve cells to figure out if and how this iron accumulation relates to neurodegenerative diseases.
The authors show that a “sustained iron overload, but not acute exposure, leads to a state of ferroptotic stress where nerve cells remain viable but become hypersensitive to oxidative injury.”
Iron, an essential mineral for the body, can be found in dark leafy greens, starchy cereals, lean meats, seafood, and other common foods.
While the exact mechanisms that initiate iron accumulation in neurons are unclear yet, the researchers suspect the buildup is caused by a failure in the cells’ iron export machinery — iron enters neurons as usual but fails to get removed after use.
They added that the question is why the failure with iron export does not impact neurons for some time.
Using a human-derived nerve cell line, the team created the first progressive model of iron accumulation in neuronal cells.
Comparing the effects of both acute (between six and eight hours) and chronic (nine days) exposure to iron, the researchers discovered an entirely new pathway, which they dubbed chronoferroptosis.
Until now, ferroptosis was considered an iron-dependent cell death pathway, with cell death dependent on a process called lipid peroxidation, they said.
Chronoferroptosis adds a dimension of time to ferroptosis and the pathway does not necessarily end in cell death — instead, the findings reveal that ferroptosis can act as a cellular stress pathway.
In acutely exposed neurons, there was very little biochemical difference pre- and post-exposure to iron.
However, in chronically exposed neurons, changes included an upregulation of some processes and downregulation of others — an accumulation of harmful chemicals and a depletion of helpful ones and an elevated lipid peroxidation.
When each exposure group was exposed to further stress, acutely exposed neurons could handle the stress, while chronically exposed neurons could not.
“It’s not the amount of iron that seals the fate of these cells, it’s the amount of time they spend under stress,” author Nawab John Dar, a postdoctoral researcher in Maher’s lab, said.
Interventions could be developed for when the brain begins to enter the vulnerable state — when iron accumulation starts stressing neurons — which could address iron imbalances and keep neurons more resilient for longer, the researchers said.
