An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production

Michele Rana, Irenaeus De Coo, Francisca Diaz, Hubert Smeets, Carlos T Moraes

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Abstract

We have isolated transmitochondrial cybrids containing a mitochondrial DNA cytochrome b 4-base pair deletion previously identified in a patient with parkinsonism. This presentation is in contrast to that of most patients with cytochrome b mutations, who present with exercise intolerance. Clones containing different levels of the cytochrome b 4-base pair deletion showed that high levels of die mutation were associated with a respiratory deficiency and a specific complex III defect. Newly synthesized full-length cytochrome b was undetectable by metabolic labeling of mutant cells, and these cells were unable to grow in media that restricts proliferation of cells with defective oxidative phosphorylation. Steady state levels of some subunits previously found to be in dose association with cytochrome b by crystallography and biochemical analysis (ie, Rieske [2Fe-2S] protein and subunit VI) were drastically reduced in clones containing high levels of the mutation, whereas the reduction in the core-1 subunit was milder. The absence of cytochrome b and complex III activity was also associated with increased hydrogen peroxide production. These findings, together with the variable tissue distribution of pathogenic mitochondrial DNA molecules, provide clues to the heterogeneous phenotypes associated with mitochondrial DNA mutations and establish a link between different forms of parkinsonism and oxidative phosphorylation defects.

Original languageEnglish
Pages (from-to)774-781
Number of pages8
JournalAnnals of Neurology
Volume48
Issue number5
DOIs
StatePublished - Nov 20 2000

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Cytochromes b
Electron Transport Complex III
Gene Deletion
Parkinsonian Disorders
Free Radicals
Mitochondrial DNA
Mutation
Oxidative Phosphorylation
Base Pairing
Clone Cells
Crystallography
Protein Subunits
Tissue Distribution
Hydrogen Peroxide
Cell Proliferation
Exercise
Phenotype

ASJC Scopus subject areas

  • Neuroscience(all)

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An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. / Rana, Michele; De Coo, Irenaeus; Diaz, Francisca; Smeets, Hubert; Moraes, Carlos T.

In: Annals of Neurology, Vol. 48, No. 5, 20.11.2000, p. 774-781.

Research output: Contribution to journalArticle

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