When Mitochondrial Genes Go Bad

Seat of the problem? Malfunction of the mitochondria (blue) may underlie problems of aging such as hypertension and high blood cholesterol.

New research points to an unexpected culprit for a constellation of symptoms similar to those experienced by people with so-called metabolic syndrome. The work, described in a paper published online 21 October in Science, shows that a mutation in a mitochondrial gene causes people to develop hypertension, high concentrations of blood cholesterol, and lower-than-normal concentrations of magnesium.

For an estimated 47 million Americans with metabolic syndrome, high blood pressure comes hand in hand with other cardiovascular risk factors such as diabetes and high blood concentrations of cholesterol and triglycerides. Obese people often have metabolic syndrome, but so do some nonobese people, so excess weight isn't the sole cause.

The new discovery, made by Richard Lifton of Yale University School of Medicine and colleagues, may help clear up the mystery. A female patient who was suffering from low blood magnesium led them to the finding. The Lifton team had previously discovered a handful of genes that, when mutated, cause this blood condition, which is characterized by general malaise and weakness. In the course of conversations with the woman, she mentioned that several of her relatives also suffered from low blood magnesium.

Further investigation turned up 142 relatives, many of whom had either low magnesium, hypertension, elevated blood cholesterol concentrations, or some combination of those problems. Even more intriguing, in all cases, the traits had been inherited from the individuals' mothers--a clear indication that the gene at fault was located inside mitochondria, subcellular structures that provide most of a cell's energy and have their own small genome. (Mitochondrial DNA is always inherited from mom.)

Analysis of the mitochondrial genome of family members turned up one mutation found only in the maternal lineage and not detected in any of the thousands of mitochondrial genomes previously sequenced. This mutation alters one base--a thymidine was changed to a cytosine--in the gene for a mitochondrial transfer RNA (tRNA), which carries amino acids to the ribosome for protein synthesis. Because virtually all tRNAs have a thymidine at that spot, implying that it's essential for the molecule's function, the swap likely disrupts the tRNA's structure and interferes with protein synthesis in the mitochondria.

Despite uncertainty about how a mitochondrial DNA mutation could lead to such diverse symptoms, hypertension expert Theodore Kurtz of the University of California, San Francisco, says that the finding "could be of tremendous importance." Previously, few cardiologists looked to the mitochondria for insight into hypertension and other cardiovascular risk factors, but this, he says, "could shift the interest dramatically."

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