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Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

Rajendran, Jayasimman ; Purhonen, Janne ; Tegelberg, Saara LU ; Smolander, Olli Pekka ; Mörgelin, Matthias LU ; Rozman, Jan ; Gailus-Durner, Valerie ; Fuchs, Helmut ; Hrabe de Angelis, Martin and Auvinen, Petri , et al. (2018) In EMBO Molecular Medicine 2018.
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
BCS1L, complex III, GRACILE syndrome, mitochondrial disorder, respiratory chain
in
EMBO Molecular Medicine
volume
2018
article number
e9456
publisher
Blackwell
external identifiers
  • pmid:30530468
  • scopus:85058170914
ISSN
1757-4676
DOI
10.15252/emmm.201809456
language
English
LU publication?
yes
id
8d302f48-0a69-44af-909b-e0a1bcb62a87
date added to LUP
2019-01-07 16:16:30
date last changed
2021-10-06 03:43:32
@article{8d302f48-0a69-44af-909b-e0a1bcb62a87,
  abstract     = {<p>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<sup>p.S78G</sup> 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.</p>},
  author       = {Rajendran, Jayasimman and Purhonen, Janne and Tegelberg, Saara and Smolander, Olli Pekka and Mörgelin, Matthias and Rozman, Jan and Gailus-Durner, Valerie and Fuchs, Helmut and Hrabe de Angelis, Martin and Auvinen, Petri and Mervaala, Eero and Jacobs, Howard T. and Szibor, Marten and Fellman, Vineta and Kallijärvi, Jukka},
  issn         = {1757-4676},
  language     = {eng},
  publisher    = {Blackwell},
  series       = {EMBO Molecular Medicine},
  title        = {Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy},
  url          = {http://dx.doi.org/10.15252/emmm.201809456},
  doi          = {10.15252/emmm.201809456},
  volume       = {2018},
  year         = {2018},
}