OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

Mitochondrion. 2020 Sep;54:113-121. doi: 10.1016/j.mito.2020.07.003. Epub 2020 Jul 18.


Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables unaffected carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G > A lymphoblasts and primary fibroblasts from both unaffected carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in cells from unaffected carrier and affected patients, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells under basal conditions, our results indicate that cells from affected patients suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in unaffected carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Cells, Cultured
  • DNA, Mitochondrial / genetics
  • Down-Regulation
  • Electron Transport Complex I / genetics*
  • Gene Expression Profiling / methods*
  • Glycolysis
  • Humans
  • Male
  • Middle Aged
  • Optic Atrophy, Hereditary, Leber / genetics*
  • Oxidative Phosphorylation
  • Penetrance*
  • Point Mutation
  • Sequence Analysis, RNA


  • DNA, Mitochondrial
  • Electron Transport Complex I