Mighty Mitochondria

Mitochondria--the intracellular organs that supply cells with energy--decline in number and activity with age. Now, some scientists think that as good mitochondria go bad, they cause a number of disorders that are associated with aging.

They are the powerhouses of the cell, the little sacks of zest that animate our bodies. Mitochondria gobble the food we eat and monopolize the air we breathe to give us the energy required to live. They even serve as the conduit of "The Force," according to the most recent Star Wars movie.

But these tiny organs inside the cell might also have a dark side. As we get older, our mitochondria slowly self-destruct, sometimes acting as a ticking bomb of degenerative disease. Recent studies have implicated unchecked mitochondrial decay in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), obesity, diabetes, and aging itself. Scientists are dissecting the inner workings of mitochondria to defuse their potential for mischief. Already, some studies have suggested that one of our most popular all-purpose panaceas--exercise--acts in part by slowing and perhaps suspending the mitochondrial countdown.

Mitochondria's capacity to cause harm comes from the same features that sustain life, says Douglas Wallace, a geneticist and mitochondrial expert at the University of California, Irvine. As the tiny cellular power plants burn oxygen, fat, and carbohydrates to produce the energy required for a cell's daily activities, they emit damaging oxygen radicals as a byproduct. Most of these toxic molecules are sopped up by antioxidant cleanup crews in the mitochondria and cell. But those that escape can injure proteins, lipids, and DNA.

One of the most vulnerable molecular targets is the mitochondria's own DNA. These small loops of genetic material, which remain separate from the well-protected chromosomes in the cell's nucleus, accumulate mutations easily.

If these genetic dings and dents disabled one or two mitochondria, the effect would be insignificant: Most cells are crammed with hundreds or thousands of these cellular batteries. But bad mitochondrial DNA spreads. Mitochondria are constantly dividing, fusing into tubular masses, and swapping bits of DNA before separating again. "At night, when you're lying awake really quiet," Wallace says, "you can almost feel them wriggling in there."

Over time, these damaged mitochondria begin to falter. They run rougher, producing less energy and dirtier emissions. To make matters worse, the energy-starved cell directs the production of more mitochondria to boost its power supply. But faulty mitochondria give rise to equally corrupt mitochondria, and without sufficient energy, the cell eventually dies.

Cell death is a central feature of many diseases of aging, including AD and Parkinson's disease. Even in cells that survive, the energy crisis probably saps the most power-hungry organs first, such as the brain, muscles, and heart. "I call it the mitochondrial paradigm of aging and degenerative disease," says Wallace.

Several recent studies support the observation that mitochondria can spur disease. In a July issue of the Proceedings of the National Academy of Sciences, Wallace and his colleagues reported that mitochondrial DNA from the brains of people with AD are more likely to have certain mutations than are those from people of the same age who did not have the disease. The genetic changes appear to sabotage the mitochondria's energy-generating process, causing a neuronal brownout, Wallace says. Also in July, a group of researchers from the University of California, San Diego, and elsewhere found that mitochondrial damage might be directly responsible for the relatively rare form of inherited ALS.

Not all mutations cause mitochondria to misbehave. Mitochondria possessing certain genetic variations work harder, consuming more calories and generating more heat than regular mitochondria. These hotter-burning mitochondria might produce fewer oxygen radicals and so are less likely to damage themselves or their host cells, says Wallace. And he finds that people with some of these souped-up mitochondria are less susceptible to AD and Parkinson's disease.

These helpful variations are more likely to be found in people whose ancestors come from certain chilly northern European regions, where the extra heat probably provided them with a selective survival advantage during the last ice age, Wallace says. Cooler-running mitochondria--typical of people from warmer climes--consume fewer calories but produce more radicals, he says. The slower-burning variations will correlate with susceptibility to metabolic diseases such as obesity and diabetes, Wallace predicts.

Endocrinologist and Howard Hughes investigator Gerald Shulman of Yale University School of Medicine has developed some of the first noninvasive imaging techniques to measure mitochondria number and function in people. Using these imaging techniques, he found that lean, healthy 70-year-olds have more fat in their muscle and liver cells and have half the number of mitochondria--and half the mitochondrial activity--as 20-year-olds of similar condition and weight. These lazy mitochondria do not burn as many calories as fully active ones do. This slowed metabolism leads to a buildup of fat in certain tissues, such as muscle and liver, which can cause insulin resistance, a condition that often leads to diabetes. He and his colleagues also found more lipid accumulation and reduced mitochondria number and activity in the muscle cells of lean, healthy college students with a strong family history of diabetes compared to those whose families were diabetes-free.

The growing weight of evidence indicting mitochondria is strong but not definitive, says gerontologist George Martin of the University of Washington, Seattle, who is collaborating with Wallace on an effort to bolster the activity of antioxidants that scrub mitochondrial emissions. Mitochondria could shape up as important, he says, but aging and aging-related diseases are likely to be about more than mitochondria. Even so, studying mitochondria could lead to novel ways to prevent or treat disease.

Until then, exercise remains one of the best medicines to enhance mitochondrial number and function. A good training program can double mitochondrial mass in the muscles that do the work, says Robert Robergs, an exercise physiologist at the University of New Mexico, Albuquerque. Robergs prescribes at least 30 minutes a day of sustained jogging, swimming, biking, or walking at an intensity at which it is hard to carry on a conversation. "You've got to actually sweat and breathe hard to get more mitochondria mass," he says. "It's not going to happen by walking the dog and accumulating 5 minutes here and there." With the proper training, people should be able to harness the power of their mitochondria and avoid looking like Jabba the Hutt.

Carol Cruzan Morton is pumping up her own mitochondria by walking, running, sea kayaking, and contemplating complex matters.