Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

J Clin Invest. 2021 Mar 15;131(6):e138267. doi: 10.1172/JCI138267.


Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.

Keywords: Genetic diseases; Genetics; Neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cell Line
  • Child, Preschool
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / metabolism*
  • Female
  • Gene Knockout Techniques
  • Genes, Recessive
  • HSP40 Heat-Shock Proteins / deficiency
  • HSP40 Heat-Shock Proteins / genetics*
  • HSP40 Heat-Shock Proteins / metabolism
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Optic Atrophy, Hereditary, Leber / genetics*
  • Optic Atrophy, Hereditary, Leber / metabolism*
  • Pedigree
  • Penetrance
  • Phenotype
  • Protein Subunits
  • Reactive Oxygen Species / metabolism
  • Young Adult


  • Dnajc30 protein, mouse
  • HSP40 Heat-Shock Proteins
  • Protein Subunits
  • Reactive Oxygen Species
  • Electron Transport Complex I