TY - JOUR
T1 - Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy
AU - Rajendran, Jayasimman
AU - Purhonen, Janne
AU - Tegelberg, Saara
AU - Smolander, Olli Pekka
AU - Mörgelin, Matthias
AU - Rozman, Jan
AU - Gailus-Durner, Valerie
AU - Fuchs, Helmut
AU - Hrabe de Angelis, Martin
AU - Auvinen, Petri
AU - Mervaala, Eero
AU - Jacobs, Howard T.
AU - Szibor, Marten
AU - Fellman, Vineta
AU - Kallijärvi, Jukka
PY - 2018
Y1 - 2018
N2 - 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 Bcs1lp.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.
AB - 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 Bcs1lp.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.
KW - BCS1L
KW - complex III
KW - GRACILE syndrome
KW - mitochondrial disorder
KW - respiratory chain
U2 - 10.15252/emmm.201809456
DO - 10.15252/emmm.201809456
M3 - Article
C2 - 30530468
AN - SCOPUS:85058170914
SN - 1757-4676
VL - 2018
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
M1 - e9456
ER -