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WHEN MITOCHONDRIA RUN AMOK:
These powerhouses of the cell belch harmful chemicals // Which tear up their surroundings // Which touches off a cycle of destruction // Which may be the culprit in a surprising range of diseases.

Energy Crisis

By Rachael Moeller Gorman // Illustrations by L-Dopa // Summer 2007
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Mitochondria

The 120 people in Barry Snow’s Phase II drug trial are clinging to the hope of a happy ending. They are still in the early stages of Parkinson’s disease, and so far symptoms are mild—a tremor every now and then, occasional stiffness in the legs. Life feels almost normal, yet they all know that without some dramatic new treatment, their long-term prognosis is not good.

If they were regular Parkinson’s patients, they could expect to return to their doctors’ offices over the next several years having trouble walking and keeping their balance and with increasingly severe tremors. Their physicians would undoubtedly prescribe the only treatment (short of surgery or physical therapy) known to ease Parkinson’s symptoms—increasing their brains’ levels of dopamine, a chemical that helps control muscle movement, often in the form of the drug levodopa (L-dopa), which has helped Parkinson’s patients since the 1960s. Yet any relief would be temporary. Their disease, with nothing to cure its root cause, would lead to a profound loss of muscle function and, eventually, dementia. Those with milder cases might lose only some muscle and brain function.

Snow, who heads the neurology department at Auckland Hospital in New Zealand, hopes the drug he’s testing will do much more than treat Parkinson’s symptoms. He believes that because his drug attacks what he and others believe is the crux of the disease, the drug will significantly slow its advance. “Then we could delay the need for L-dopa,” he says.

The target of Snow’s drug is fairly novel in the realm of disease treatment, although it should be familiar to anyone who has taken high school biology. He’s aiming for mitochondria—tiny powerhouses in every cell—which recent research shows may play an important role in the progression of Parkinson’s. The problem could be an overabundance of destructive reactive oxygen species (called ROS, and which include a particular type called free radicals) in the mitochondria; the drug, MitoQ, gets inside these organelles and mops up free radicals. MitoQ has been in development since the late 1990s, when biochemist Mike Murphy and organic chemist Robin Smith at the University of Otago in New Zealand developed it; since then, its effects have been studied in human cells and animals.

If MitoQ is able to slow the progression of Parkinson’s, it might also be effective in treating other diseases believed to result, at least in part, from a falloff in mitochondrial function. Studies during the past 10 years have identified a host of common disorders with apparent ties to mitochondria, including type 2 diabetes, cancer, even aging. Each disease is different, with unique triggers and symptoms, and much of the science seeking to establish mitochondria’s role is still in the early stages and could fail to confirm causal links. Yet the potential payoff is considerable. If mitochondria prove to be involved with varied disease processes, they could become a major target of treatment.

Two billion years ago (give or take a few hundred million), a bacterium invaded a larger single-celled organism. Because the bacterium was very good at something the single cell needed—making energy—the cell kept it around. During millions of years of dividing and evolving, the bacterium became the mitochondrion, which powers almost every cell in every multicelled organism, helping the organism digest food, beat its heart and move its muscles. Cells now have hundreds or even thousands of mitochondria.

To generate energy, mitochondria manipulate sugars. First, a cell breaks apart glucose into a smaller molecule called pyruvate, which the cell then imports intoa mitochondrion. Via a multistep process, the mitochondrion strips each pyruvate molecule of its carbon atoms to create two other molecules, reduced nicotinamide adenine dinucleotide (NADH) and 1,5-dihydroflavin adenine dinucleotide (FADH2). Machinery within the mitochondria, the electron transport chain, extracts electrons from NADH and FADH2 and pumps positively charged protons into the intermembrane space (mitochondria have two cell membranes). The protons are then drawn back inward to the negatively charged mitochondrial matrix at the mitochondrion’s center, and as they surge across the membrane, they turn a waterwheel-like molecule, adenosine triphosphate (ATP) synthase. That generates energy, which is stored in ATP and used by every cell and organ in the body.

Mitochondria’s 37 genes code for the manufacture of key proteins and helper molecules in the energy production pathway (including the electron transport chain) and are all inherited from the mother’s mitochondria-packed egg. In 1981 Nobel laureate Frederick Sanger and his colleagues in Cambridge, England, determined the sequence of these genes. That enabled researchers to compare mitochondrial DNA in healthy people with that in patients suffering from a number of rare, maternally inherited diseases. Scientists eventually discovered 50 mutations and linked them to a series of devastating disorders known by such acronyms as MELAS, LHON and MERRF. In all these diseases, the genetic mutations have crippled the mitochondria’s energy-producing machinery.

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When Mitochondria Mutate

Mutations in the mitochondrion’s 37 genes point clearly to certain rare disorders.

Is This Why We Get Old?

Mitochondrial deterioration, fueled by free radicals, may speed the aging process. But the link is far from certain.

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1. Power, Sex, Suicide: Mitochondria and the Meaning of Life, by Nick Lane (Oxford University Press, 2005). A tale of mitochondria’s evolution from free-floating, single-celled bacteria to the most important organelles in our bodies.

2. “Powerhouse of Disease,” by Nick Lane, Nature, March 2006. A fascinating summary of the hunt for nuclear genes that encode mitochondrial proteins, detailing the role such genes play in initiating a variety of common diseases.

3. “Mitochondria, Oxidants, and Aging,” by Robert S. Balaban et al., Cell, Feb. 25, 2005. Balaban presents a clear picture of the mitochondrial theory of aging, supported by studies of aging worms, flies and mice.

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