Bouncer at the Energy Bar: Mitochondrial proteins kick out radicals (Oxidative stress)
Authors: Beckman Mary 
Published: August 2003

Like bouncers at a bar, several proteins appear to eject molecular hellions from a cellular chamber where they could cause trouble. The miscreants--reactive oxygen species (ROS) such as superoxide--have been implicated in aging. Primarily byproducts of cellular energy production, ROS damage other molecules due to their highly reactive nature: Also known as oxygen radicals, ROS break chemical bonds in DNA, proteins, and fats (see
"The Two Faces of Oxygen"
). The molecules in the center of mitochondria are particularly at risk of being roughed up by ROS, because that's where most of these destructive molecules are created. Now biochemists have discovered that a family of proteins called uncoupling proteins (UCPs) might provide some protection: Perhaps they boot superoxide radicals out of the middle of mitochondria and stuff them into spaces where they can be detoxified.

Some researchers postulate that mitochondria can limit ROS production by generating heat rather than the energy-carrying molecule adenosine triphosphate (ATP). The two processes start out the same: Biochemical reactions in the mitochondrial center pump protons into its intermembrane space, where they're stored like water in the reservoir of a hydroelectric dam; this first step also generates ROS. The protons flow back across the inner membrane through turbinelike complexes, creating ATP in the process. Routing the protons around the turbines--"uncoupling" the proton flow from ATP formation--can (but doesn't always) create heat. Animals can exploit this process: For example, hibernating bears use uncoupling to stay warm in the winter. A protein called UCP1 helps accomplish this task: It causes protons to seep through the membrane, allowing the energy from fatty acid consumption to be converted into heat rather than stored in ATP. Researchers have proposed that the leaky membrane creates an environment in the center of the mitochondria that impedes ROS generation. They don't know whether UCP1 reduces amounts of ROS, but recent experiments on rats have shown that two related proteins also found in humans, UCP2 and UCP3, cut down on the quantities of the destructive molecules. These proteins' activities are perplexing, however: UCP2 and UCP3 don't create heat, and although they're related to UCP1, they also resemble a family of proteins that transport negatively charged molecules across membranes. Some ROS, including superoxide, carry a negative charge.

Brand and colleagues wanted to explore further how UCPs affect ROS levels. The researchers examined mitochondria from a variety of rat tissues that contain UCPs. They incubated the mitochondria from different sources with ROS-generating chemicals. The group found that an abundance of ROS caused the reservoir to leak protons across the mitochondrial inner membrane--an indication of uncoupling. Further tests showed that the induced leak depended on the presence of fatty acids, any one of the three UCPs, and superoxide. Peroxide, a different ROS, did not trigger the proton leak. These results suggest that superoxide itself, through the action of UCPs, puts a cap on its accumulation in the middle of the mitochondria.

The researchers haven't pinned down how superoxide and UCPs work together, nor how this collaboration might allow UCP2 and UCP3 to decrease superoxide concentrations, as observed previously. Promoting proton seepage might upset the electron-rich environment necessary to create ROS. Alternatively, Brand suggests--partly on the basis of unpublished observations and the UCPs' resemblance to transporter proteins--that the UCPs might bounce superoxide out of the mitochondrial centers and into the intermembrane space, where the radical molecules can be inactivated. Future experiments aim to uncover this potential transport mechanism, but in the meantime, the new results tighten a connection between the UCP proteins and an important ROS. Next, researchers can enfeeble these molecular security guards to probe how unregulated superoxide affects aging.

--Mary Beckman

K. S. Echtay, D. Roussel, J. St-Pierre, M. B. Jekabsons, S. Cadenas, J. A. Stuart, J. A. Harper, S. J. Roebuck, A. Morrison, S. Pickering, J. C. Clapham, M. D. Brand, Superoxide activates mitochondrial uncoupling proteins.
Nature
415
, 96-99 (2002).
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