File:Kearns-Sayre, OS, C, FA, Palma, Gilbert, 010588-01.jpg

Relation between genetic and biochemical findings in mitochondrial disease. (A) Maternally inherited mtDNA (green circles, semicircles, and fragments) can have large-scale single deletions, rearrangements, or point mutations (yellow star). If a threshold level of heteroplasmy is exceeded, activity of complexes I, III, IV, or V will be variably affected depending on the site of the mutation or size of the deletion. Complex II activity remains unaffected. (B) Autosomal dominant inheritance of a nuclear DNA mutation (red star) in genes responsible for mtDNA replication machinery (polymerase gamma and Twinkle helicase) results in multiple deletions of mtDNA, with variable effects on the activity of complexes I, III, IV, and V. Complex II activity remains unaffected because the effect of the mutation is exerted through proteins synthesised by mtDNA. Some autosomal dominant mutations, in genes such as OPA1 and MFN2, affect mitochondrial integrity, and can cause either mtDNA depletion or multiple deletions. (C) Autosomal recessive mutations (homozygous or compound heterozygous) in nuclear DNA genes that encode polymerase gamma and Twinkle helicase, might lead to either depletion or multiple deletions of mtDNA. Again, because these autosomal recessive mutations affect mtDNA, the resulting biochemical abnormalities might affect complexes I, III, IV, and V alone, or in various combinations, but complex II activity is unaffected. (D) Autosomal recessive mutations in nuclear DNA genes encoding protein subunits of respiratory chain complexes, proteins governing the assembly of complexes, or the electron carrier coenzyme Q10 can cause isolated biochemical deficiencies of the corresponding complex or, in the case of coenzyme Q10, a biochemical abnormality evident on a linked assay of complexes II and III. mtDNA copy number remains normal and there is no evidence of multiple deletions. mtDNA=mitochondrial DNA.

Courtesy of Douglas M. Turnbull FRCP