Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

EMBO Mol Med. 2019 Jan;11(1):e9456. doi: 10.15252/emmm.201809456.


Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII)-deficient Bcs1l p.S78G knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.

Keywords: BCS1L; GRACILE syndrome; complex III; mitochondrial disorder; respiratory chain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / prevention & control*
  • Cell Respiration*
  • Ciona intestinalis / enzymology
  • Ciona intestinalis / genetics
  • Electron Transport Complex III / deficiency*
  • Gene Knock-In Techniques
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Plant Proteins / genetics
  • Plant Proteins / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • Survival Analysis


  • Mitochondrial Proteins
  • Plant Proteins
  • Recombinant Proteins
  • Oxidoreductases
  • alternative oxidase
  • Electron Transport Complex III