Dysfunctional mitochondrial maintenance: what breaks the circle of life?

Despite being recognized as the first Mendelian-inherited mitochondrial disorders (Zeviani et al ., 1990), it has taken over a quarter of a century to realize that disorders of mitochondrial DNA maintenance form a large proportion of the patients seen in adult neurogenetics clinics. Most conditions were initially identified in families presenting with the ‘classical’ mitochondrial phenotype of late-onset chronic progressive external ophthalmoplegia and bilateral ptosis. However, several papers published in Brain in the last 2 years have shown that the field may have been barking up the wrong (phenotypic) tree. The clinical manifestations associated with disorders of mitochondrial DNA maintenance are proving to be much more heterogeneous than was initially understood; and, interestingly, one of the more recently implicated nuclear genetic defects, OPA1 , is a major player in the stability of the mitochondrial network. This principle comes to the fore yet again in this issue of Brain , strongly suggesting that the burden of human disease associated with the accumulation of somatic mitochondrial DNA abnormalities and disturbed mitochondrial dynamics will expand further, whilst providing valuable mechanistic insight of much broader pathophysiological relevance.First defined at the molecular level in 2001 (Van Goethem et al ., 2001), large pedigrees with autosomal dominant chronic progressive external ophthalmoplegia due to mutations in POLG are well established and now feature routinely in neurology and ophthalmology textbooks. POLG codes for the only DNA polymerase present within mitochondria, polymerase γ, and mutations in this nuclear gene lead to point mutations and the accumulation of mitochondrial DNA deletions throughout life (Chan and Copeland, 2009). A combination of clonal expansion and recurrent mutation drive the level of these mutations upwards within individual cells (see Box 1 for a detailed explanation). When the percentage level exceeds a critical threshold, the cells express a biochemical defect that can affect …