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.
Highlights
Mitochondrial disorders are the most common class of inherited errors of metabolism
We show that Alternative oxidase (AOX), a non-mammalian enzyme that can bypass complex III (cIII) blockade by shunting electrons directly from the quinone pool to oxygen, is able to permanently prevent lethal cardiomyopathy and alleviate multiple other pathologies in cIII-deficient GRAC mice
We found that, in the C57BL/6JCrl background, the homozygotes survive to median P210 and develop lethal cardiomyopathy after P150, a manifestations not seen in the GRACILE syndrome patients with early neonatal lethality, but a common manifestation in other mitochondrial disorders
Summary
Mitochondrial disorders are the most common class of inherited errors of metabolism. effective treatments are lacking, and their clinical management remains largely supportive (Pfeffer et al, 2013). In patients with RC cIII (ubiquinol:cytochrome c oxidoreductase) deficiency, mutations in several genes encoding either cIII subunits or assembly factors have been identified. These compromise cIII enzymatic activity and result in a wide variety of clinical manifestations (Fernandez-Vizarra & Zeviani, 2015). BCS1L mutations are the most common cause of cIII deficiency, with various neonatal and adult phenotypes described worldwide (Fernandez-Vizarra & Zeviani, 2015), the most severe and prevalent of them being GRACILE syndrome (fetal growth restriction, aminoaciduria, cholestasis, liver iron overload, lactic acidosis, and early death during infancy) (Fellman et al, 1998; Visapaaet al, 2002). Homozygous Bcs1lc.A232G (Bcs1lp.S78G) knock-in mice bearing the GRACILE syndrome-analogous mutation recapitulate many of the clinical manifestations, including growth failure, progressive hepatopathy, kidney tubulopathy, and, in a C57BL/6JCrlBomTac background, short survival of 35 days
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