Sci. Aging Knowl. Environ., 8 February 2006
Mucking With Metabolism
Inability to repair DNA damage in mitochondria could foster metabolic syndrome
In some family businesses, one heir will strike out in a new direction, rejecting his or her expected fate. Similarly, a protein whose kin protect animals from cancer instead seems to guard mice against a metabolic disruption. The results show that flawed DNA repair could contribute to a condition called metabolic syndrome, and they support a link between the condition and mitochondria.
Interfering with genes that normally fix problems in nuclear DNA causes many types of cancer (see "Dangerous Liaisons"). Researchers discovered a DNA repair gene called neil1 4 years ago; they have since found altered versions of it in human stomach cancers. Vartanian and colleagues wanted to find out more about this gene.
As a first step, they generated mice that lacked both copies of the neil1 gene, expecting an increase in cancer incidence. Instead, the mice became obese and lethargic. This observation surprised the researchers because deleting related DNA repair genes does not cause those problems. Whereas normal mice weigh about 28 grams, some of the engineered rodents topped 50 grams. Also unexpectedly, their cancer incidence did not surge. The scientists wondered whether the mice suffered from a rodent version of metabolic syndrome, a condition that predisposes people to kidney and heart disease as well as diabetes. Humans suffering from metabolic syndrome do not metabolize fats and sugars correctly. Although researchers have yet to pin down its cause, some scientists think that malfunctioning mitochondria, which squeeze energy from fats and sugars, contribute. The protein NEIL1 and its relatives fix DNA in the mitochondria as well as the nucleus, so defective forms of the enzyme might allow mitochondrial DNA to remain bashed-up and compromise the organelle's activities.
Further investigation showed that fat riddled the animals' livers, and watery cavities pockmarked their kidney cells. Kidney disease is a hallmark of metabolic syndrome, but its relationship to these cavities is unknown. Large concentrations of insulin and triglycerides, fat building blocks, muddied the rodents' blood. These results suggest that the mice have metabolic syndrome. The researchers confirmed that mitochondrial DNA from the engineered mice sports an unusually large number of breaks.
Together, the findings hint that unattended damage to mitochondrial DNA--presumably from the oxidative assaults that accompany energy production (see "The Two Faces of Oxygen")--hobbles the organelles' normal functioning and leads to metabolic syndrome, says cell biologist Susan LeDoux of the University of South Alabama, Mobile. Calling the result "a very exciting piece of work," biochemist William Copeland of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, says, "This is the first example of DNA repair being involved in metabolic syndrome." NEIL1 also mends DNA in the nucleus, however, so it's not yet clear how much the mitochondrial damage provokes the syndrome. No one knows why the loss of NEIL1 generates symptoms so different from those associated with its molecular relatives. "NEIL1 could recognize a unique lesion in DNA," whereas the others might perform overlapping jobs, suggests LeDoux. If the work holds up in humans, enhancing the activity of NEIL1 might help this molecular black sheep perform its rebel endeavors.
February 8, 2006
Science of Aging Knowledge Environment. ISSN 1539-6150