Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

Research output: Contribution to journalArticle


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 Bcs1lp.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.


  • Jayasimman Rajendran
  • Janne Purhonen
  • Saara Tegelberg
  • Olli Pekka Smolander
  • Matthias Mörgelin
  • Jan Rozman
  • Valerie Gailus-Durner
  • Helmut Fuchs
  • Martin Hrabe de Angelis
  • Petri Auvinen
  • Eero Mervaala
  • Howard T. Jacobs
  • Marten Szibor
  • Vineta Fellman
  • Jukka Kallijärvi
External organisations
  • Folkhälsan Research Center
  • University of Helsinki
  • Helmholtz Zentrum München
  • German Center for Diabetes Research
  • Technical University of Munich
  • University of Tampere
  • Helsinki University Central Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Physiology


  • BCS1L, complex III, GRACILE syndrome, mitochondrial disorder, respiratory chain
Original languageEnglish
Article numbere9456
JournalEMBO Molecular Medicine
Publication statusPublished - 2018
Publication categoryResearch