Mitochondrial DNA haplogroups and ageing mechanisms in osteoarthritis.

MITOCHONDRIAL DNA AND AGEING Osteoarthritis (OA) is the most common form of arthritis affecting more than 12% of people over the age of 60. Although late-onset articular cartilage degeneration is common and age is one of the most important risk factors for the disease, the relationship between old age and OA is not fully understood. In the past it was believed that the link with age was due to ‘wear and tear’ of articular cartilage by continuous mechanical stress; we now know, however, that OA involves an active response to injury comprising remodelling of articular cartilage and subchondral bone, in addition to synovial inflammation and damage to other joint structures such as ligaments and menisci. Biological ageing is a complex process and it is now widely accepted that ageing starts with molecular damage, leading to cell, tissue and, ultimately, organ dysfunction. Extensive evidence from animal models and in vitro studies indicates that mitochondria contribute to specific aspects of the ageing process, including cellular senescence, chronic inflammation and the age-dependent decline in stem cell activity. Perhaps the best known and most longstanding hypothesis to explain ageing is the free radical theory that proposes a central role for the mitochondrion as the principal source of intracellular reactive oxygen species (ROS) leading to mitochondrial DNA (mtDNA) mutations. 5 Somatic (acquired) mtDNA mutations and their association with the decline in mitochondrial function during ageing are well described, but these observations do not necessarily imply a causal relationship between mitochondrial dysfunction and human ageing. The maternally inherited mtDNA sequences encode the key proteins involved in energy production, although the relevance of high sequence variability of mtDNA had been considered of little functional relevance. Latorre-Pellicer and coauthors showed recently that transferring mtDNA from a mouse strain to the nuclear DNA (nDNA) background of another strain results in huge differences in insulin signalling, obesity and longevity throughout the life of the mouse. The two mtDNA sequences differ in genetic variants that confer 12 amino acid substitutions and 12 changes in RNA molecules involved in mitochondrial protein synthesis; this level of variation is enough to result in striking differences in the ROS generation, insulin signalling, obesity and cell-senescence-related parameters such as telomere shortening and mitochondrial dysfunction. Showing the direct relevance of mtDNA in human ageing and in age-related diseases, such as OA, is a big challenge and one which is, at least in part, addressed in this issue.