What Happens When Cells Run Out of Fuel

Inside almost every cell in the body are microscopic powerhouses known as mitochondria. Theory has it that some 1.5 billion years ago, mitochondria were independent cells, probably bacteria, and that they were swallowed up by the cells of higher organisms in need of quick energy. That's what mitochondria do for cells -- produce quick energy, explains MDA grantee Douglas Wallace of Emory University in Atlanta, who's been studying them for more than a decade.

Mitochondria (singular, mitochondrion) have their own DNA (genes), but their function is also governed by genes in the cell's nucleus, the main command center. They operate under a sort of dual-control system.

mitochondrion and cell nucleus diagram

About 90 percent of the energy needed by the body's tissues is made by the mitochondria, which store it in a molecule known as ATP, the end result of a long chain of chemical events. ATP then has to be carried out of the mitochondria into the main part of the cell.

Mitochondrial disorders, including mitochondrial myopathies (muscle disorders related to mitochondria malfunctions), can result from abnormalities in DNA inside the mitochondria or DNA in the cell's nucleus that affects mitochondria.

Now, two mouse models of mitochondrial myopathy have been developed to help scientists get a foothold on solving some of the mysteries of this kind of disorder. In the first model, Wallace and his colleagues at Emory bred mice without functioning genes for the protein known as ANT1. (The ANT1 gene is in the cell's nucleus.) This protein normally ferries ATP from the mitochondria into the main part of the cell. Without it, ATP builds up in the mitochondria and can't satisfy the cell's energy needs.

The ANT1-deficient mice had enlarged hearts, muscles with "ragged red" fibers, a sign of abnormal mitochondria in humans, and they couldn't exercise very well at all -- the same symptoms seen in many humans with mitochondrial disorders.

Wallace notes that there have been no humans found with ANT1 deficiency but, he says, no one is ruling out that some mitochondrial myopathies could be caused by this defect.

Wallace says the ANT1-deficient mouse model is the first clear demonstration that there is a cause-and-effect relationship between a limited supply of ATP (the energy molecule) and the physiologic effects seen with mitochondrial myopathies.

Meanwhile, a group of researchers at the University of Alabama at Birmingham and the University of Iowa have developed another mouse model of mitochondrial myopathy and tested a gene therapy strategy on these mice.

These researchers used a mouse with a natural genetic mutation in a gene for a mitochondrial enzyme known as SCAD. The gene is in the cell's nucleus. Defects in the SCAD gene have been found in children and cause various metabolic and muscle abnormalities. (The SCAD enzyme is normally found in the liver, kidneys, skeletal muscles and heart.)

The researchers bred the mice until they had rodents completely lacking in this crucial mitochondrial enzyme, which normally contributes to ATP production.

They then went a step further. They wanted to see whether replacing SCAD would cure the mitochondrial disorder. Using transgenic engineering, the investigators added back genes for SCAD and safely corrected the energy deficiency in the tissues of the mice. The researchers suggest that gene therapy with the SCAD gene, perhaps directed only at the liver (an organ that's easy to reach and that's vitally affected in SCAD deficiency), should be investigated as a treatment possibility.

The ANT1-deficient mouse paper is in the July issue of Nature Genetics, and the SCAD-deficient mouse study is in the September issue of Human Molecular Genetics.


"This is a pretty big deal," David Housman, a biology professor at the Massachusetts Institute of Technology in Cambridge told The New York Times in an Aug. 8 story. "We have turned a corner from looking at genes to where we can begin developing real assays for drugs." He was talking about Huntington's disease, a neurodegenerative brain disorder; but he might just as well have been talking about several other disorders, including spinal-bulbar muscular atrophy (Kennedy's disease) and several of the autosomal dominant spinocerebellar ataxias (at least SCA types 1, 2, 3, 6 and 7).

What do these seemingly different diseases have in common? Their genetic cause -- an expanded section of DNA containing too many repeated sequences of the chemicals cytosine, adenine and guanine, or CAG.

Since they were first noted in the early 1990s, the list of so-called "triplet repeat" disorders has grown enormously. CAG repeats are among the best understood of this group.

DNA is a code, or recipe, for the manufacture of proteins. CAG is the code for glutamine, a component of some proteins. Too many CAG codes and you get too many glutamine molecules.

What the Huntington's disease researchers were so excited about was the finding that too many glutamine molecules in a protein caused the protein to clump up in the cell's nucleus, eventually leading to the death of the cell.

There was an abnormal protein "bunched up into a huge ball of crud inside the nucleus," Stephen Davies, an anatomy professor at University College in London, England, told the Times reporter about the Huntington's disease findings, which his group reported in the Aug. 8 issue of Cell.

Dr. Kenneth Fischbeck, professor of neurology at the University of Pennsylvania and a long-time MDA grantee, also has an interest in CAG repeats and the disorders associated with them. It was his group that first identified CAG repeats as the cause of SBMA. This summer, he was among researchers who found brain cells with protein clumps in spinocerebellar ataxia type 3. His group published its work in the August issue of Neuron.

Fischbeck believes the causes of all CAG repeat diseases, at the protein and DNA levels, are the same, although the protein affected in each disease is different, and the cells that are affected may be different. These differences account for the varying characteristics in each neurodegenerative condition.

"The findings are consistent with a common mechanism for these diseases," Fischbeck says, "based on protein aggregation [clumping] and toxicity to neurons. Any new insight into a disease mechanism brings us closer to rational, effective treatment for these diseases."

The mechanism appears to be similar among the "polyglutamine diseases," he says. "The expanded poly-glutamine repeats cause the proteins to aggregate, and this presumably interferes with some cellular process, such as gene expression or RNA processing, and eventually leads to the death of the cell." (RNA is the chemical step between DNA and protein.)

Sounds grim, but Fischbeck is optimistic. "To me, the most exciting thing about the recent findings is that they point to possible therapeutic intervention. The protein aggregation appears to be precipitated by proteolysis [digestion of the proteins]. If so, we may be able to devise a treatment to block the proteolysis or otherwise interfere with the protein aggregation. Cell culture and animal models have now been developed to test such treatments. If a treatment works in the cultured cells and in animals, then it would have a good chance of working in patients. Because of the shared mechanism, effective treatment for any one of these diseases could well work for the others."


In Lambert-Eaton myasthenic syndrome (LEMS), fluctuating weakness occurs because the immune system makes antibodies against nerve endings that release a signal-carrying chemical, acetylcholine. A study done at the University of Alabama at Birmingham and the Veterans Affairs Medical Center there says the drug known as guanidine, combined with pyridostigmine (Mestinon), is helpful and not too toxic in LEMS. Guanidine, previously thought by many doctors to be too toxic for routine use, increases secretion of acetylcholine from the nerve endings. Pyridostigmine decreases the breakdown of acetylcholine so that more of it is available to stimulate muscles. The study is in the September issue of Muscle & Nerve.


Corticosteroids, drugs in the prednisone family, are often used to treat autoimmune diseases like polymyositis, dermatomyositis, myasthenia gravis and Lambert-Eaton myasthenic syndrome. They're also sometimes used in Duchenne muscular dystrophy. These drugs, while sometimes very effective, also have serious side effects, one of the most important being osteoporosis -- loss of bone, largely through decreasing the amount of calcium people can absorb from food or calcium supplements.

A Canadian study in the Aug. 7 issue of the New England Journal of Medicine reports that combining calcium supplements with the drug etidronate (Didronel) on a rotating schedule reduced bone loss and fractures in people taking prednisone-like drugs better than did calcium therapy alone. Calcium is a normal component of bone, and etidronate attaches to bone and stabilizes bone.


An MDA-backed research group at San Francisco's California Pacific Medical Center, headed by MDA clinic director Dr. Robert Miller, is testing the drug gabapentin (Neurontin) as a treatment for spinal muscular atrophy types 2 and 3. The drug is also being tested at nine other North American centers.

People who qualify for the drug trial will need confirmation of their SMA diagnosis by genetic testing and must have adequate respiratory function (determined by a test known as forced vital capacity). The trial will last a year.

Some participants will receive gabapentin, which appears to interfere with formation of the natural substance glutamate, and others will receive a placebo (inert substance). Gabapentin is already on the market for seizure disorders and is being tested at California Pacific and elsewhere for use in amyotrophic lateral sclerosis. Glutamate is toxic to nerve cells if there's too much of it, or if a damaged or immature cell can't process it properly -- as may be the case in SMA.

For further information about the San Francisco trial, call Giovanna Kushner at (415) 923-3604. For information about the other centers' trials, call MDA at (800) 572-1717, or check MDA's Web site at