New Insights on Rotenone Resistance of Complex I Induced by the m.11778G>A/ MT-ND4 Mutation Associated with Leber's Hereditary Optic Neuropathy

Molecules. 2022 Feb 16;27(4):1341. doi: 10.3390/molecules27041341.

Abstract

The finding that the most common mitochondrial DNA mutation m.11778G>A/MT-ND4 (p.R340H) associated with Leber's hereditary optic neuropathy (LHON) induces rotenone resistance has produced a long-standing debate, because it contrasts structural evidence showing that the ND4 subunit is far away from the quinone-reaction site in complex I, where rotenone acts. However, recent cryo-electron microscopy data revealed that rotenone also binds to the ND4 subunit. We investigated the possible structural modifications induced by the LHON mutation and found that its amino acid replacement would disrupt a possible hydrogen bond between native R340 and Q139 in ND4, thereby destabilizing rotenone binding. Our analysis thus explains rotenone resistance in LHON patients as a biochemical signature of its pathogenic effect on complex I.

Keywords: LHON; complex I; mtDNA mutations; rotenone.

MeSH terms

  • Alleles*
  • Amino Acid Sequence
  • Amino Acid Substitution*
  • Binding Sites
  • Conserved Sequence
  • Drug Resistance / genetics*
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Models, Molecular
  • Mutation*
  • Optic Atrophy, Hereditary, Leber / genetics*
  • Optic Atrophy, Hereditary, Leber / metabolism
  • Protein Binding
  • Protein Conformation
  • Rotenone / chemistry
  • Rotenone / pharmacology*
  • Structure-Activity Relationship
  • Uncoupling Agents / pharmacology

Substances

  • Uncoupling Agents
  • Rotenone
  • Electron Transport Complex I