Somatic mutations in mitochondria: the chicken or the egg?

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases. However, the pathophysiological mechanisms are still not fully understood and the etiology is simply unknown. Biomedical researchers have investigated various aspects of this intricate disease. Da Sylva and colleagues have now analyzed yet another piece in the 'RA-puzzle'. In a recent article in Arthritis Research & Therapy, this group analyzed the presence of mitochondrial DNA (mtDNA) mutations in patients with RA and their possible role in the pathogenesis of RA [1]. The sequencing of RNA transcribed from the mitochondrial MT-ND1 gene showed a higher mutational burden (that is, changes per base pair) in RA cultured fibroblasts and RA tissue than in cells and tissue from patients with osteoarthritis (OA). More importantly, in RA tissue significantly more of these mutations resulted in non-synonymous amino acid changes than those in tissues of patients with OA.Mutations in mtDNA have long been thought to have a role in the pathogenesis of various diseases. The 'classic' mitochondrial syndromes like Leigh syndrome or Leber's hereditary optic neuropathy are caused by inherited (germline) mutations of mtDNA. They comprise a wide spectrum of clinical symptoms that arise as a result of dysfunction of the mitochondrial respiratory chain, mostly affecting tissues that are highly dependent on oxidative metabolism such as the nervous system or the eye [2]. In contrast, tissue-specific accumulation of somatic (non-inherited) mtDNA mutations is best described in various types of cancer. Somatic mtDNA mutations have been found in breast cancer, colorectal cancer, renal cell carcinoma, malignant glioma and hematologic malignancies, to name only a few (reviewed in [3]). Furthermore, it was suggested that mtDNA mutations are involved in the development of cardiac disease [4] and neurodegenerative disorders such as Alzheimer's disease [5]. Finally, accumulated mtDNA mutations due to oxidative damage a