Targeting the alternative oxidase (AOX) for human health and food security, a pharmaceutical and agrochemical target or a rescue mechanism?

Abstract

Some of the most threatening human diseases are due to a blockage of the mitochondrial electron transport chain (ETC). In a variety of plants, fungi, and prokaryotes, there is a naturally evolved mechanism for such threats to viability, namely a bypassing of the blocked portion of the ETC by alternative enzymes of the respiratory chain. One such enzyme is the alternative oxidase (AOX). When AOX is expressed, it enables its host to survive life-threatening conditions or, as in parasites, to evade host defenses. In vertebrates, this mechanism has been lost during evolution. However, we and others have shown that transfer of AOX into the genome of the fruit fly and mouse results in a catalytically engaged AOX. This implies that not only is the AOX a promising target for combating human or agricultural pathogens but also a novel approach to elucidate disease mechanisms or, in several cases, potentially a therapeutic cure for human diseases. In this review, we highlight the varying functions of AOX in their natural hosts and upon xenotopic expression, and discuss the resulting need to develop species-specific AOX inhibitors.

Transcriptome Analyses in Adult Olive Trees Indicate Acetaldehyde Release and Cyanide-Mediated Respiration Traits as Critical for Tolerance against Xylella fastidiosa and Suggest AOX Gene Family as Marker for Multiple-Resilience

“…A hypothesis that we think is valuable to be validated. Also, microbiota and parasites were shown to profit from own AOX or PTOX genes [ 79 , 80 , 81 ]. Thus, we suggest exploring furthermore the role of alternative respiration within plant holobiont system-components for plant stress-relief [ 40 , 82 ] and functional marker development.…”

“…In this way, highly efficient functional marker development and further developed strategies for gene editing could be supported that can expect to improve Xf -tolerance and multiple-resilience. Nevertheless, strategies that aim to target AOX genes for genetic engineering, gene editing and therapeutic inhibition should carefully consider specific knowledge that was discussed in Aziz et al [ 12 ] and Szibor et al [ 80 ].…”

Alternative Oxidase: From Molecule and Function to Future Inhibitors

“…As a result, the activities of different AOXs exhibit inconsistency. To address this, certain scholars emphasized the importance of designing AOX inhibitors that are specific to particular species, which arise from the distinct functions of AOX in its natural host and xenotopic expression …”