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Rajendran, J.* ; Purhonen, J.* ; Tegelberg, S.* ; Smolander, O.P.* ; Mörgelin, M.* ; Rozman, J. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Auvinen, P.* ; Mervaala, E.* ; Jacobs, H.T.* ; Szibor, M.* ; Fellman, V.* ; Kallijärvi, J.*

Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy.

EMBO Mol. Med. 10:e9456 (2018)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Bcs1l ; Complex Iii ; Gracile Syndrome ; Mitochondrial Disorder ; Respiratory Chain; Iron-overload; Nitric-oxide; Mouse Model; Expression; Gene; Protein; Oxygen; Cell; Activation; Defects
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Zeitschrift EMBO Molecular Medicine
Quellenangaben Band: 10, Heft: 12, Seiten: , Artikelnummer: e9456 Supplement: ,
Verlag Wiley
Verlagsort Chichester
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)