Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere9456
JournalEMBO Molecular Medicine
Volume2018
DOIs
Publication statusPublished - 2018

Subject classification (UKÄ)

  • Physiology

Free keywords

  • BCS1L
  • complex III
  • GRACILE syndrome
  • mitochondrial disorder
  • respiratory chain

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