Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

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http://hdl.handle.net/10138/298764

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Rajendran , J , Purhonen , J , Tegelberg , S , Smolander , O-P , Mörgelin , M , Rozman , J , Gailus-Durner , V , Fuchs , H , de Angelis , M H , Auvinen , P , Mervaala , E , Jacobs , H T , Szibor , M , Fellman , V & Kallijärvi , J 2019 , ' Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy ' , EMBO molecular medicine , vol. 11 , no. 1 , 9456 . https://doi.org/10.15252/emmm.201809456

Title: Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy
Author: Rajendran, Jayasimman; Purhonen, Janne; Tegelberg, Saara; Smolander, Olli-Pekka; Mörgelin, Matthias; Rozman, Jan; Gailus-Durner, Valerie; Fuchs, Helmut; de Angelis, Martin Hrabe; Auvinen, Petri; Mervaala, Eero; Jacobs, Howard T.; Szibor, Marten; Fellman, Vineta; Kallijärvi, Jukka
Other contributor: University of Helsinki, University of Helsinki
University of Helsinki, University of Helsinki
University of Helsinki, Anna-Elina Lehesjoki / Principal Investigator
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Eero Mervaala / Principal Investigator
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Clinicum
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program












Date: 2019-01
Language: eng
Number of pages: 19
Belongs to series: EMBO molecular medicine
ISSN: 1757-4676
DOI: https://doi.org/10.15252/emmm.201809456
URI: http://hdl.handle.net/10138/298764
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 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.
Subject: BCS1L
complex III
GRACILE syndrome
mitochondrial disorder
respiratory chain
IRON-OVERLOAD
NITRIC-OXIDE
MOUSE MODEL
EXPRESSION
GENE
PROTEIN
OXYGEN
CELL
ACTIVATION
DEFECTS
3111 Biomedicine
1184 Genetics, developmental biology, physiology
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