San Diego: Uncouplers Keep Mitochondria Burning Clean—Protect Neurons

Series - Society for Neuroscience Annual Meeting 2004:

Next time you ponder the pros and cons of coal burning power plants, consider this: Mitochondria, our cellular power plants, do a great job keeping us supplied with ATP, but they, too, have emission problems. As electrons cascade down the mitochondrial respiratory chain, like water down a hydroelectric shaft, they can leak out of the inner membrane to partially reduce oxygen, forming such reactive oxygen species (ROS) as superoxide radicals and hydrogen peroxide. ROS, of course, damage proteins and nucleic acids, and have been implicated in aging and neurodegenerative disease, most notably Alzheimer (see ARF related news story) and Parkinson disease, which can be elicited by chemicals that damage the respiratory chain.

How can we prevent electrons from leaking? At hydroelectric dams there’s a simple solution to a similar problem. When water pressure builds, the flood gates are opened and the water harmlessly bypasses the turbine. Not surprisingly, nature has an equally simple solution for mitochondria—uncouplers.

Uncouplers were the focus of several presentations at the Society for Neuroscience meeting in San Diego this past week. Embedded in the mitochondrial membrane, they are so named because they uncouple the electron transport chain (the river upstream) from ATP synthase (the turbine), allowing electrons to flow rapidly to their final destination, cytochrome c oxidase. Uncouplers minimize leakage, and hence ROS production, allowing the vast majority of electrons to end up in one of the most harmless molecules of all, water. Zane Andrews and colleagues working at Tamas Horvath’s lab at Yale University reported that expression of uncoupler protein 2 (UCP2) regulates the amount of mitochondrial ROS formed, and can protect dopaminergic neurons of the substantia nigra, which are the very cells that are damaged in Parkinson disease.

Andrews made transgenic mice that either overexpressed UCP2 or had it knocked out completely (see Meeting Abstract No. 903.13). To measure ROS produced by mitochondria in vivo, he perfused the animals with a single tail injection of dihydroethidium, which is converted to the fluorescent ethidium in the presence of superoxide. When Andrews used fluorescent microscopy to examine mitochondria isolated from dopaminergic neurons, he found that the amount of ethidium, and hence superoxide, was substantially reduced in the mice overexpressing the uncoupler, while in the UPC2 knockout animals, it was substantially higher than wild-type. In addition, overexpression of UCP2 increased respiratory chain uncoupling as judged by the amount of oxygen consumed by the cells.

But could uncouplers be exploited to reduce production of ROS and protect dopaminergic cells of the substantia nigra? Apparently so. When Andrews challenged the animals with MPTP, a mitochondrial toxin that achieved notoriety in the 80’s when it was found to be responsible for inducing Parkinson disease in heroin addicts, he found twice as many neurons in the substantia nigra of animals overexpressing the uncoupler than were found in wild-type animals also treated with the toxin. In addition, MPTP-treated UPC2 knockouts had 40 percent fewer neurons than did wild-type animals. The findings indicate that uncoupling mitochondria can provide some protection in a chemical simulation of Parkinson disease.

This work was supported by research from Bruno Conti at Tamas Bartfai’s lab at the Scripps Research Institute (see Meeting Abstract No. 94.9). Conti also described overexpression of UCP2, but this time under the control of the tyrosine hydroxylase promoter, which restricted expression of the transgenic protein to dopaminergic cells. Conti first showed that the additional UCP2, twice as much as found in wild-type animals, appeared only in the substantia nigra and locus coerulus, the latter also being affected in PD. Conti found that oxygen consumption was increased in animals overexpressing the uncoupler, and this was accompanied by a decrease in ROS. Lipid peroxidation and protein carbonylation, two measures of oxidative damage, were also reduced, and the transgenic animals were protected from MPTP—about 60 percent more neurons survived in transgenic animals than in controls.

Any attempt to use uncouplers as a therapeutic will have to be carefully controlled because uncoupling the respiratory chain completely would be lethal. But there may be subtle ways to modulate the electron transport chain and keep mitochondria running “cleaner.” Andrews reported, for example, that fatty acids (in this case palmitate) led to about a twofold, significant increase in electron transport chain uncoupling, suggesting that dietary modulation may be beneficial to our mitochondrial health, and ultimately, to us. Alzforum readers are no strangers to debate about caloric restriction and mitochondrial function, both of which are implicated in aging and the pathology of neurodegenerative diseases.—Tom Fagan.

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