Rajendran 2019 EMBO Mol Med

Rajendran J, Purhonen J, Tegelberg S, Smolander OP, Mörgelin M, Rozman J, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Auvinen P, Mervaala E, Jacobs HT, Szibor M, Fellman V, Kallijärvi J (2019) Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy. EMBO Mol Med 11:e9456.

» PMID: 30530468 Open Access

Rajendran J, Purhonen J, Tegelberg S, Smolander OP, Moergelin M, Rozman J, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Auvinen P, Mervaala E, Jacobs HT, Szibor M, Fellman V, Kallijaervi J (2019) EMBO Mol Med

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.

© 2018 The Authors. Published under the terms of the CC BY 4.0 license. • Keywords: BCS1L, GRACILE syndrome, Complex III, Mitochondrial disorder, Respiratory chain, Alternative oxidase • Bioblast editor: Plangger M • O2k-Network Lab: DE Jena Szibor M, FI Helsinki Mervaala E, FI Helsinki Jacobs HT

Labels: MiParea: Respiration, nDNA;cell genetics, Genetic knockout;overexpression 

Stress:Mitochondrial disease  Organism: Mouse  Tissue;cell: Heart, Liver, Kidney  Preparation: Isolated mitochondria  Enzyme: Complex III 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, CIV, NS  HRR: Oxygraph-2k, O2k-Fluorometer 

2019-01, AmR