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Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy.

EMBO Mol. Med. 10:e9456 (2018)
Publishers Version DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
as soon as is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Bcs1l ; Complex Iii ; Gracile Syndrome ; Mitochondrial Disorder ; Respiratory Chain; Iron-overload; Nitric-oxide; Mouse Model; Expression; Gene; Protein; Oxygen; Cell; Activation; Defects
Reviewing status