Alternative oxidase‐mediated respiration prevents lethal mitochondrial cardiomyopathy

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.

Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

“…To rule out the possibility that the period of anoxia was not sufficient, we replicated the experiments with an extended period of anoxia (30 minutes), which essentially gave the same results (Figure B‐E). Together with previous findings of AOX activity in the heart under various conditions, we concluded that a functional impairment of AOX is an unlikely explanation for the lack of cardioprotection against I/R injury, and that, therefore, all observed phenomena can mechanistically be attributed to catalytic AOX activity interfering with the mitochondrial respiratory chain and specifically to the restoration of the electron flux through the ETC.…”

“…To rule out the possibility that the period of anoxia was not sufficient, we replicated the experiments with an extended period of anoxia (30 minutes), which essentially gave the same results ( Figure S1B-E). Together with previous findings of AOX activity in the heart under various conditions, 33,38,40 we concluded that a functional…”

“…In the present study, we tested how respiratory restoration by AOX affects the development of I/R injury and adaptive remodelling in the mouse heart. Our data demonstrate that AOX, despite being sufficiently expressed and catalytically active in the healthy and diseased mouse heart, fails to confer either acute or chronic cardioprotection, despite respiratory restoration. Instead, AOX expression fosters long‐term adverse remodelling and cardiac contractile impairment.…”

Alternative oxidase confers nutritional limitation on Drosophila development

“…In accordance with this, the ubiquitous expression of Ciona AOX in both flies (Fernandez‐Ayala et al, ) and mammals (Szibor et al, ) has almost no detectable physiological effect under nonstressed conditions. However, if the standard respiratory chain is dysfunctional, for example, due to toxic inhibition (El‐Khoury et al, ; Fernandez‐Ayala et al, ; Szibor et al, ), overload (Mills et al, ), or genetic damage (Kemppainen et al, ; Rajendran et al, ), AOX is able to compensate the resulting phenotypes to a significant degree. However, since AOX bypasses two of the proton‐pumping steps of the standard respiratory chain, it is not able to fully restore ATP production.…”

Sea squirt alternative oxidase bypasses fatal mitochondrial heart disease

“…The sea squirt alternative oxidase (AOX) is able to bypass the distal part of the MRC and was shown to alleviate the consequences of CIII and CIV defects in several cellular and Drosophila models. In this issue of EMBO Molecular Medicine, Rajendran et al (2019) demonstrate the first proof of concept in mammals, by showing that AOX is capable to extend lifespan and prevent heart failure in a CIII deficient mouse model, raising the possibility of future human AOX bypass treatment. EMBO Mol Med (2019) 11: e9962 See also: J Rajendran et al (January 2019) M itochondria are intracellular organelles with a separate genome (mtDNA) and translation system, present in all enucleated cells.…”