Plugging the Mitochondrial Leak

FEATUREThe Longevity Dividend Plugging the Mitochondrial LeakBY NICK LANEWhy does an elephant live twenty times longer than a mouse? Partly just because it's bigger, but even after correcting for body mass, mammals with fast metabolic rates (high oxygen consumption), such as mice, age and die swiftly, whereas animals with slow metabolic rates, such as elephants, live longer and age more slowly.ILLUSTRATION BY JOELLE BOLTM

Mar 1, 2006
Nick Lane
FEATURE
The Longevity Dividend

Plugging the Mitochondrial Leak

Why does an elephant live twenty times longer than a mouse? Partly just because it's bigger, but even after correcting for body mass, mammals with fast metabolic rates (high oxygen consumption), such as mice, age and die swiftly, whereas animals with slow metabolic rates, such as elephants, live longer and age more slowly.

ILLUSTRATION BY JOELLE BOLT
Mitochondria have different strategies for minimizing oxidative stress. (A) In the respiratory chain, reduced complexes (red) are generally more reactive than oxidized complexes (blue) and therefore generate more free radicals (). (B) Polymorphisms in mtDNA can lead to low free-radical leakage despite strongly reduced complexes. (C) Uncoupling of the respiratory chain leads to fast electron flow and low leakage due to relatively oxidized complexes. (D) Larger surface area for mitochondrial membranes, with the same number of electrons entering overall, produces mainly oxidized complexes.?(E) Smaller surface area generally means more reduced complexes, but because there are fewer complexes in total available to react with oxygen, overall free-radical leakage is low.

While an inverse correlation between resting metabolic rate and longevity in animals generally holds true, there are some exceptions to the rule. Birds, bats, and humans live several times longer than their metabolic rates would suggest. The reason lies in the rate at which reactive oxygen species (ROS) leak out of the mitochondrial respiratory chain, the succession of membrane-bound proteins that passes electrons from NADH to oxygen. According to Gustavo Barja at the Complutense University in Madrid, pigeons leak barely a tenth the ROS of rats, and live nearly ten times longer, yet their resting metabolic rates are similar. "ROS leakage is so low in pigeons that they can afford to have much lower antioxidant levels than rats, and still live longer," says Barja. "The question is, why are pigeon mitochondria so leak-proof?"

The answer could have profound implications. According to Alan Wright at Edinburgh University, the cellular threshold for apoptosis is calibrated by the rate of ROS leakage: "Species that leak ROS slowly have a lower rate of apoptotic cell loss in degenerative conditions, including those that apparently have nothing to do with oxidative or nitrosative stress." Analyzing single mutations in 10 different degenerative conditions across five species, Wright and collaborators found that age of onset and severity of disease correlates closely with the rate of ROS leakage. "If we could slow ROS leakage, there's a prospect we could delay the onset of a wide spectrum of degenerative diseases," he says.

In June 2005, Douglas Wallace's group at the University of California, Irvine, showed that the approach could work in mammals.1 They generated transgenic mice that overexpress the antioxidant enzyme catalase in mitochondria (to break down hydrogen peroxide). Not only are average and maximal lifespans increased by about five months, but also degenerative conditions such as cardiac pathology and cataract formation are delayed.

Other work suggests that antioxidants targeted to the mitochondria, such as mitoQ, concentrate 1000-fold in the mitochondrial matrix, where they inhibit apoptosis. But antioxidants have the potential to interfere with ROS signaling, which plays a major role in the physiology of the cell. Birds solve the problem by cutting leakage from complex I, not by raising intramitochondrial antioxidant levels.

"The critical factor determining ROS leakage is not antioxidant status but the redox state of complex I, which is the major source of ROS," says Martin Brand at the MRC Dunn Unit in Cambridge, UK. "Redox state is dependent on numerous factors like substrate supply, ATP use, uncoupling, amount of complexes, and allosteric influences, such as Ca2+ activation or NO inhibition of cytochrome oxidase. So predicting the outcome depends on knowing the state of all these variables."

Such variables explain conundrums such as the exercise paradox-why physically active people don't die early. During exercise, the flow of electrons down the respiratory chain quickens, as does oxygen consumption. The overall effect is greater oxidation of complex I, and lower leakage.

A fall in the reduction state of complex I explains other apparent anomalies, such as the long lifespan of mice with high resting metabolic rates. Brand, working with John Speakman and colleagues at the University of Aberdeen, showed that these mice had more uncoupling proteins in their mitochondria, enabling electron flow to be uncoupled from ATP production, dissipating energy as heat. Uncoupling meant they consumed more oxygen at rest, yet they lived longer than other mice.2

Uncoupling may be important in people, too. Mitochondrial DNA haplotypes vary geographically, with some types predominant in tropical regions, others in colder climes. The pattern might reflect differing degrees of uncoupling, restricting internal heat generation in hot climates, and vice versa. A consequence might be a higher rate of ROS leak in tropical peoples, and a correspondingly higher susceptibility to degenerative conditions such as heart disease.

Intervention might be possible. Vladimir Skulachev at Moscow State University points to recent work showing that the reduction state of complex I depends strongly on the NAD+ and NADH levels. "Perhaps we could lower ROS leakage, and correspondingly apoptosis, by maintaining a tighter control over the NADH pool."

References
1. S.E. Schriner et al., "Extension of murine life span by overexpression of catalase targeted to mitochondria," Science, 308:1909-11, 2005.
2. J.R. Speakman et al., "Uncoupled and surviving: Individual mice with high metabolism have greater mitochondrial uncoupling and live longer," Aging Cell, 3:87-95, 2004.
3. A.D. Vinogradov, V.G. Grivennikova, "Generation of superoxide-radical by the NADH:ubiquinone oxidoreductase of heart mitochondria," Biochemistry (Mosc), 70:120-7, 2005.