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When Mitochondria, the Cell's Energy Producers, Get Sick In retrospect, it was clear from the moment Samantha Fargo was born six years ago that something was very wrong - and very strange. At first, she was too weak to breast feed. By five weeks, she could drink from a bottle, but had such bad reflux (in which food backs up the esophagus from the stomach) that her parents, Justine and Bill Fargo of Medford, had to keep her semi-upright all the time. She didn’t walk until she was a year and a half old. Worse yet, the poor kid never seemed to have much energy. This spring, she developed gastroparesis, in which her stomach and intestines stopped functioning, prompting a long hospitalization. She is now fed via a tube in her stomach and another in a vein. Yet it wasn’t until she was four that Samantha’s symptoms gelled into a diagnosis: mitochondrial disease ___ an often-underdiagnosed genetic problem that may shed light on far more common problems, including energy loss with aging and disorders of later life such as Alzheimer’s, Parkinson’s, diabetes and heart disease. Conservatively, mitochondrial disease is believed to affect between 40,000 to 70,000 Americans, says Christopher Rice, executive director of the United Mitochondrial Disease Foundation. But in reality, the disorders may be ‘’extremely common’’ and frequently missed by doctors, says Doug Wallace, a mitochondrial DNA geneticist who heads the new Center for Molecular and Mitochondrial Medicine at the University of California, Irvine. The mitochondria are the powerhouses of the cell, little ‘’organelles’’ ---- 1,000 per cell --- that, in the presence of oxygen, convert the energy stored in hydrogen bonds in fat and sugar into the kind of energy the body can use, a substance called ATP (adenosine triphosphate). The chemistry is complicated, but essentially, energy is passed through an electron transport chain in and out of five ‘’complexes’’ or processing areas. At each step, different enzymes come into play. In the final step, an electrical charge glues the components of ATP together. If the mitochondria don’t work properly, the result is a lack of energy and ultimately, cell death. But mitochondrial disease can be tough to diagnose because lack of energy is a symptom of many diseases. And unlike diseases that attack one main organ, mitochondrial dysfunction can affect multiple organs, especially the brain and muscles. In some cases, mitochondrial dysfunction is caused by drugs, including the cholesterol-lowering drugs called statins, and certain AIDS drugs, notes Dr. Bruce Cohen, a neurologist at the Cleveland Clinic Foundation in Ohio. Over the course of a lifetime, free radicals, destructive oxygen molecules, also damage the mitochondria. This is a major reason why scientists suspect that mitochondrial damage underlies many of the diseases of later life, notes Wallace of UC/Irvine. Indeed, a recent study by Howard Hughes Medical Institute investigators at Yale University found that a decline in mitochondrial function is linked to insulin resistance, a precursor to diabetes. But perhaps the most dramatic instances of mitochondrial disease are those caused in children by genetic defects. The exact figure is unknown, but mitochondrial disease is believed to occur in one in 2,500 to one in 4,000 births, notes Dr. Mark Korson, associate chief of the metabolism service at Boston’s Floating Hospital for Children, part of Tufts-New England Medical Center. There are two ways to inherit mitochondrial disease: via defects in the mitochondrial DNA itself, or by defects in genes in the nucleus that act in the mitochondria. The former can only be inherited in a matriarchal fashion, through defects in the mother’s mitochondrial DNA. (Samantha’s mother, for instance, has a mild form of the disease herself.) The latter can come from defects in either parent’s nuclear DNA. The reason for this duality is that the DNA in mitochondria actually came, about 2 billion years ago, from a bacterium that was engulfed by a cell with a nucleus. Over the eons, some of the mitochondrial genes migrated to the nucleus. At some point in the cell division cycle, mitochondrial DNA duplicates itself (as DNA in the nucleus also does) and the mitochondria flock to one daughter cell or another. But within any given cell, some mitochondria may be normal and some sick, a state called heteroplasmy. Depending on how the mitochondria sort themselves out during cell division, some of the new cells may get a lot of bad mitochondria while others do not. This explains why some siblings, even identical twins, can end up with mitochondrial problems of vastly differing severity. There are no high-tech cures for mitochondrial diseases, but some low-tech remedies, chiefly vitamin supplements, can help, though much of the data on this is anecdotal. In theory, one might think that giving people ATP would correct the low energy problem. Unfortunately, this doesn’t work; ATP is such a short-lived molecule that a person would have to consume several times her body weight in ATP every day. A better solution is what doctors call a “mito cocktail,’’ says Dr. Richard Kelley, director of metabolism at the Kennedy Krieger Institute at Johns Hopkins University. One ingredient of this cocktail is coenzyme Q-10, an enzyme that, in natural form, drives energy production in the mitochondria. Depending on which stage of energy production in the mitochondria is affected, boosting coenzyme Q-10 levels may help. Coenzyme Q10 also functions as an antioxidant, which means it may help repair mitochondrial damage caused by free radicals. Another component of the supplement cocktail is carnitine, which is also made naturally by the body and binds to intermediate products in the energy production chain. Vitamins such as thiamine (B1) and riboflavin (B12) may help, too, as can the antioxidant vitamins C and E, and another supplement lipoic acid. At the University of Florida, Dr. Peter Stacpoole, director of the general clinical research center, has been exploring other approaches. One is a drug called DCA (dichloroacetate) that may block the buildup of lactic acid that can occur in mitochondrial disorders. Another, based on the idea that sick mitochondria can’t process carbohydrate properly, is a (high fat) “ketogenic” diet, in which the body, in particular the brain, uses fat instead of carbohydrate for fuel. Farther down the pipeline, scientists hope to tinker with what Wallace of UC/Irvine calls the mitochondrial ‘’switch’’ that helps control electrical conductivity in mitochondria. For the moment, though, except for the “mito cocktails” and common sense measures like eating a healthy diet, it’s still an uphill battle for families like the Fargos. When things flare up, says Samantha’s mother Justine, things get ‘’pretty awful. I wish I had more hope that scientists will come up with a cure soon.’’
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