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CORVALLIS, Ore. - Researchers have discovered that mitochondria, the so-called powerhouses of cells, contain an unequal distribution of DNA building-blocks, or nucleotides - a finding that may help explain the high rate of mutation of mitochondrial genes, and ultimately shed light on the cause of some diseases and even the aging process.

The research has been published in Proceedings of the National Academy of Sciences, a professional journal, by scientists from Oregon State University and the National Institutes of Health.

"The nucleus of most cells has roughly equal levels of the nucleotides A, C, T, and G, which are the chemical precursors of DNA," said Christopher Mathews, a distinguished professor emeritus of biochemistry and biophysics at OSU. "This is important for genomic stability. But when we explored the levels of these nucleotides in the mitochondria of some cells, we were surprised to find that they were highly unequal."

In the study of rat tissues, the scientists found that in mitochondria from skeletal muscles and the heart, the nucleotide "G" made up almost 90 percent of the total, and "T" was almost nonexistent.

It's not certain what the evolutionary value of this "asymmetry" in mitochondrial nucleotides may be, Mathews said, but it's clear that it could play a role in driving errors in DNA replication, and may be related to some disease processes, including neurodegenerative diseases, heart disease and cancer.

Mitochondrial DNA also accumulates mutations with age, and the resulting decline in function could be a key to the process of aging.

Mitochondria are present within the cell but outside the nucleus, have their own DNA, and can replicate. The mitochondrion is often called the "powerhouse" of the cell and is a place of considerable oxidative activity - it carries out the oxidation of nutrients and releases energy for other life functions. But this oxidation process is also a source of ultimate damage to DNA, proteins and membranes.

Scientists have also learned that the mitochondrial genome has a rate of mutation that is 10 to 100 times higher than that of nuclear genes. Genetic mutation can be important in evolution - it sets the stage for changes in species, is the key to biological diversity, and is also valuable in some biological systems such as the immune system. But mutations can also lead to cell dysfunction, cell death and diseases.

What's now clear, as well, is that there is a great deal more variation in the nucleotides making up mitochondria than in levels of DNA building blocks elsewhere in the cell.

"We don't really know yet why the nucleotide levels in mitochondria are so asymmetric," Mathews said. "Elevated mitochondrial mutagenesis may reflect oxidative damage to their DNA, or inefficient mitochondrial DNA repair processes, or the asymmetry itself could be a driving force behind DNA mutation."

An in-vitro analysis of DNA replication showed that if all the DNA precursors were available in balanced proportions, DNA replication was highly accurate. But if they were greatly unbalanced, as can occur in mitochondria, there was a much higher frequency of replication errors, Mathews said.

This is the first demonstration that natural asymmetry in DNA precursor pools can cause replication errors leading to mutations, the researchers say.

At least one possibility, Mathews said, is that if the rate of mitochondrial mutation is high from birth, it may explain the age-related accumulation of mitochondrial mutations, leading to decline in mitochondrial function and the biological symptoms associated with aging. A method that successfully slowed down this rate of mutation in mitochondria might also slow the aging process, he said.

These studies were funded by the National Science Foundation and the U.S. Army Research Office.