Sci. Aging Knowl. Environ., 16 July 2003
Plugging a Deadly Leak
Mitochondrial protein fortifies the brain against stroke
Key Words: ischemia mitochondrial permeability transition ischemic preconditioning
A sturdy helmet has saved many a baseball player and motorcyclist from head injury. But the brain is not as fragile and helpless as it seems. It fights back against stroke and other insults, and new work reveals one of its weapons. The study identifies a protein that fends off injury from stroke, probably by preventing leaks in mitochondria that eventually spur cells to kill themselves.
By shutting off blood flow, a stroke starves brain cells of oxygen and nutrients, but damage worsens after circulation resumes. One reason is that mitochondria, the organelles that power the cell, leak compounds that spur the activation of a protein known as caspase-3, which goads cells to kill themselves. However, researchers have known for more than a decade that a small stroke can lessen the severity of later ones, suggesting that the brain protects itself. Neurobiochemist Karoly Nikolich of AGY Therapeutics in South San Francisco and colleagues wanted to learn how.
The researchers triggered small strokes in rats and determined which genes boosted their output. One stood out: It coded for uncoupling protein-2 (UCP-2), one of five related proteins that cut energy output by mitochondria (see Nicholls Perspective). Previous studies indicated that UCP-2 might trim obesity and exacerbate diabetes, but its role in the brain remained uncertain. To determine whether UCP-2 shields neurons, the team deprived rat brain cells of oxygen and glucose for 90 minutes. These conditions killed 40% of neurons engineered to make extra UCP-2 and 90% of control cells. Like dead batteries, mitochondria from control cells lost their electrical charge, indicating that they had sprung leaks, but organelles from engineered cells remained powered up. Because leaking mitochondria awaken caspase-3, the researchers measured the killer protein's activity. Altered neurons harbored much less activated caspase-3 than did controls.
To learn whether UCP-2 works similarly in animals, the researchers stimulated strokes in mice by closing an artery that feeds part of the brain, then they measured the resulting lesions. Brain scars covered three times the area in control mice as did scars in mice engineered to pump out excess UCP-2. Together, the results suggest that UCP-2 shields brain cells from stroke damage, probably by stanching the mitochondrial leakiness that incites caspase-3. Rousing UCP production might help ameliorate stroke and neurodegenerative diseases that involve misbehaving mitochondria, such as Parkinson's disease and Alzheimer's disease (see "Mitochondrial Mayhem"), says Nikolich.
The findings are important because they begin to unravel how the protein guards brain cells, says neuroscientist Mark Mattson of the National Institute on Aging in Baltimore, Maryland. However, boosting UCP-2 output doesn't prove that the protein normally performs the same function, he cautions. To resolve that issue, researchers must determine whether reducing amounts of UCP-2 increases vulnerability to stroke damage. The uncoupling proteins hail from a sprawling extended family, and the study raises the question of whether other members of the clan normally help shelter the brain, says neurologist Stuart Lipton of the Burnham Institute in La Jolla, California. He adds that the work provides researchers with a target to manipulate; such investigations might reveal treatments that can help the brain help itself.
--Mitch Leslie; suggested by Amir Sadighi Akha
July 16, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150