Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

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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 .

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
Contributor organization: University of Helsinki
Anna-Elina Lehesjoki / Principal Investigator
Research Programs Unit
Research Programme for Molecular Neurology
Institute of Biotechnology
DNA Sequencing and Genomics
Eero Mervaala / Principal Investigator
Department of Pharmacology
Lastentautien yksikkö
Children's Hospital
STEMM - Stem Cells and Metabolism Research Program
HUS Children and Adolescents
Date: 2019-01
Language: eng
Number of pages: 19
Belongs to series: EMBO molecular medicine
ISSN: 1757-4676
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
3111 Biomedicine
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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