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EMBO Mol Med. 2019 Jan;11(1). pii: e9456. doi: 10.15252/emmm.201809456.

Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy.

Author information

1
Folkhälsan Research Center, Helsinki, Finland.
2
Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
3
Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden.
4
Molecular Neurology Research Program and Neuroscience Center, University of Helsinki, Helsinki, Finland.
5
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
6
Division of Infection Medicine, Clinical Sciences, Lund University, Lund, Sweden.
7
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
8
German Center for Diabetes Research (DZD), Neuherberg, Germany.
9
Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, TU Munich, Freising-Weihenstephan, Germany.
10
Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
11
Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
12
Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
13
Folkhälsan Research Center, Helsinki, Finland jukka.kallijarvi@helsinki.fi.

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.

KEYWORDS:

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

PMID:
30530468
PMCID:
PMC6328925
DOI:
10.15252/emmm.201809456
[Indexed for MEDLINE]
Free PMC Article

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