Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy

Mauro Degli Esposti, Valerio Carelli, Anna Ghelli, Marina Ratta, Massimo Crimi, Simonetta Sangiorgi, Pasquale Montagna, Giorgio Lenaz, Elio Lugaresi, Pietro Cortelli

Research output: Contribution to journalArticlepeer-review

Abstract

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH: ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH: ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.

Original languageEnglish
Pages (from-to)375-379
Number of pages5
JournalFEBS Letters
Volume352
Issue number3
DOIs
Publication statusPublished - Oct 3 1994

Keywords

  • LHON
  • Mitochondrial DNA
  • NADH: ubiquinone reductase
  • Ubiquinone

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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