1 June 2004. Despite the efforts of a league of DNA proofreading and copyediting enzymes, the genetic code that keeps us all alive is not impervious to mutation. Some mutations are innocuous, while others can cut us down in our prime. Most mutations occur in the nuclear DNA, but what about the mitochondrial genome? In fact, mutations there are responsible for a slower kind of demise, namely premature ageing. This is the conclusion of a report in the 27 May issue of Nature by Nils-Goran Larsson and colleagues, at Karolinska University in Stockholm.
Data linking mitochondrial DNA (mtDNA) mutations with ageing has been around for some time, but it has been mainly correlative. Now, Larsson and colleagues put cause and effect together. By genetically engineering mice with a mitochondrial DNA polymerase that is prone to proofreading errors, they show that mitochondrial mutations are a direct cause of early ageing.
First author Aleksandra Trifunovic and colleagues focused on the mitochondrial polymerase PolgA. Though this DNA copy machine is prone to mistakes, it fortunately possesses a proofreading capability that enables it to check the copy it just made against the original and remove errors. Also fortunate is that the copying and editing activities are housed in different parts of the enzyme, as this allowed Trifunovic to inactivate only the proofreading part and introduce the now-mutagenic PolgA into mice.
The results were profound. As predicted, the mice did pick up random mutations in the mitochondrial DNA much faster than wild-type animals. For example, by eight weeks mutant animals had about nine mutations per 10 kilobases of DNA, while normal mice had less than one. But it was the physiology of the animals that was most pronounced. At first they looked normal, but by about 25 weeks of age (that’s early adulthood to a mouse), they started to show signs of premature ageing. The animals stopped gaining weight and became bald. Low bone mineral density curved their spines in a sign of clinical osteoporosis. Half of the animals were dead by 48 weeks and 61 weeks, respectively, much sooner than the typical lab mouse, which lives about two years.
“These findings strongly support the idea that mutations in mitochondrial DNA can cause at least some features resembling ageing,” write ARF advisor George Martin and Lawrence Loeb, both from University of Washington, Seattle, in an accompanying news and views. They also agree that the results are consistent with the “oxidative damage” theory of ageing, the hypothesis that reactive oxygen species, generated by the mitochondrial respiratory chain, cause tissues to age. Trifunovic and colleagues found, for example, that respiration rates were lower in the hearts of the mutant mice and that respiratory chain enzyme activities were substantially reduced, “consistent with the suggestion that the deficiencies were induced by mutations of mtDNA,” the authors write.
Whether these findings can be directly translated to humans is unclear at present. There are known cases where the proofreading capability of human mtDNA polymerase is mutated. This leads to a condition called progressive external ophthalmoplegia, which causes paralysis of the eye muscles. As Martin and Loeb point out, mitochondrial DNA proofing may not be the only pathway that generates abnormalities resembling ageing. There are other nuclear proofreading enzymes, for example, and it will be interesting to see if mutations in these have similar effects.
“Of higher priority, however, would be experiments aimed at finding ways of maintaining the structure and function of tissues and organs for longer periods,” write Martin and Loeb. In this regard, the PolgA mutants may be a valuable tool to assess dietary or pharmacological interventions that affect reactive oxygen species, suggest Larsson and colleagues.—Tom Fagan.
Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson N-G. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429:417-423. Abstract
Martin GM, Loeb LA. Mice and mitochondria. Nature. 2004 May 27;429:357-358. Abstract