Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

Abstract

Cardiac ischaemia‐reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re‐perfused post‐ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post‐anoxic heart mitochondria. However, post‐ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up‐regulated upon I/R such as the atrial natriuretic peptide (Anp) whilst expression of pro‐fibrotic and pro‐apoptotic transcripts were increased. Ex vivo analysis revealed contractile failure at nine but not 3 weeks after ischaemia whilst label‐free quantitative proteomics identified an increase in proteins promoting adverse extracellular matrix remodelling. Together, this indicates an essential role for ETC‐derived signals during cardiac adaptive remodelling and identified ROS as a possible effector.

Coenzyme Q redox signalling and longevity

“…However, AOX expression in flies did not rescue mutations in tko (fly orthologue of the human MRPS12) [95], sesB (orthologue of the Adenine Nucleotide Translocator, ANT 1) [96], mtDNA-helicase (orthologue of Twinkle) or tamas [97]. Furthermore, AOX lowers survival of mice carrying a muscle-specific mutation of COX15 [98], aggravates symptoms associated with cardiac arrest, despite preventing ROS-RET, in mouse models where heart circulation is interrupted [99] and severely shortens lifespan of flies under thermal stress, hypoxia and hyperoxia [42].…”

“…Paradoxically, mice expressing AOX are not protected against ischemia-reperfusion and in the long-term accumulate more cellular damage than the controls [99]. Similarly, AOX expression in mice carrying a mutation in Cox15 shortens the already reduced survival of these mutants [98].…”

Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active

“…Remarkably, in most cases this has been achieved without producing adverse phenotypic effects, at least under standard physiological conditions, i.e., in the absence of metabolic stress signaling related to respiratory disruption [ 7 ]. By enabling electron flow through cI and other ubiquinone reductases, AOX can maintain the mitochondrial membrane potential, thus supporting ATP production, and blunt the excessive production of reactive oxygen species when the respiratory chain is impaired [ 6 , 17 ]. Furthermore, AOX expressed in mouse was shown to alleviate the acute lethal effects of cyanide administration [ 7 ] and of LPS endotoxemia [ 18 ], attenuate cigarette smoke-induced lung damage [ 19 ], and block hypoxia-induced pulmonary vasoconstriction in an ex vivo setting [ 20 ], illustrating its potential for use in future therapy against diseases associated with ETC dysfunction.…”

Mitochondria Isolated from Hearts Subjected to Ischemia/Reperfusion Benefit from Adenine Nucleotide Translocase 1 Overexpression

“…In addition, improvement in mitochondrial function does not always translate into a reduction in infarct size. This was shown by M. Szibor et al [44]. The respiratory enzyme AOX (alternative oxidase) preserved the electron flux of stressed mitochondria and attenuated ROS production but had no benefit for the infarction size of the heart during the acute phase of I/R (30 ischemia/120 reperfusion) in AOX overexpressing mice.…”