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The cytochrome b p.278Y>C mutation causative of a multisystem disorder enhances superoxide production and alters supramolecular interactions of respiratory chain complexes

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  • Anna Ghelli
  • Concetta V Tropeano
  • Maria Antonietta Calvaruso
  • Alessandra Marchesini
  • Luisa Iommarini
  • Anna Maria Porcelli
  • Claudia Zanna
  • Vera De Nardo
  • Andrea Martinuzzi
  • Flemming Wibrand
  • John Vissing
  • Ivana Kurelac
  • Giuseppe Gasparre
  • Nur Selamoglu
  • Fevzi Daldal
  • Michela Rugolo
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Cytochrome b is the only mtDNA-encoded subunit of the mitochondrial complex III (CIII), the functional bottleneck of the respiratory chain. Previously, the human cytochrome b missense mutation m.15579A>G, which substitutes the Tyr 278 with Cys (p.278Y>C), was identified in a patient with severe exercise intolerance and multisystem manifestations. In this study, we characterized the biochemical properties of cybrids carrying this mutation and report that the homoplasmic p.278Y>C mutation caused a dramatic reduction in the CIII activity and in CIII-driven mitochondrial ATP synthesis. However, the CI, CI + CIII and CII + CIII activities and the rate of ATP synthesis driven by the CI or CII substrate were only partially reduced or unaffected. Consistent with these findings, mutated cybrids maintained the mitochondrial membrane potential in the presence of oligomycin, indicating that it originated from the respiratory electron transport chain. The p.278Y>C mutation enhanced superoxide production, as indicated by direct measurements in mitochondria and by the imbalance of glutathione homeostasis in intact cybrids. Remarkably, although the assembly of CI or CIII was not affected, the examination of respiratory supercomplexes revealed that the amounts of CIII dimer and III2IV1 were reduced, whereas those of I1III2IVn slightly increased. We therefore suggest that the deleterious effects of p.278Y>C mutation on cytochrome b are palliated when CIII is assembled into the supercomplexes I1III2IVn, in contrast to when it is found alone. These findings underline the importance of supramolecular interactions between complexes for maintaining a basal respiratory chain activity and shed light to the molecular basis of disease manifestations associated with this mutation.
Original languageEnglish
JournalHuman Molecular Genetics
Volume22
Issue number11
Pages (from-to)2141-51
Number of pages11
ISSN0964-6906
DOIs
Publication statusPublished - 1 Jun 2013

ID: 41953592