Abstract
Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems. In Drosophila pupal development, attenuated JNK signaling in the thoracic dorsal epithelium leads to defective midline closure, resulting in cleft thorax. Here we report that concomitant expression of the Ciona intestinalis alternative oxidase (AOX) was able to compensate for JNK pathway downregulation, substantially correcting the cleft thorax phenotype. AOX expression also promoted wound-healing behavior and single-cell migration in immortalized mouse embryonic fibroblasts (iMEFs), counteracting the effect of JNK pathway inhibition. However, AOX was not able to rescue developmental phenotypes resulting from knockdown of the AP-1 transcription factor, the canonical target of JNK, nor its targets and had no effect on AP-1-dependent transcription. The migration of AOX-expressing iMEFs in the wound-healing assay was differentially stimulated by antimycin A, which redirects respiratory electron flow through AOX, altering the balance between mitochondrial ATP and heat production. Since other treatments affecting mitochondrial ATP did not stimulate wound healing, we propose increased mitochondrial heat production as the most likely primary mechanism of action of AOX in promoting cell migration in these various contexts.
Highlights
Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems
In this study, we showed that the expression of alternative oxidase (AOX) is able to promote cell migratory behavior in two different models: in Drosophila, AOX expression corrected thoracic closure defects produced by impaired signaling at several steps in the JNK pathway, while AOX-expressing immortalized mouse embryonic fibroblasts (iMEFs) showed enhanced migration, which was abolished by JNK inhibitor V
AOX was unable to correct cell migration defects resulting from downregulation of the main JNK substrate, the c-Jun subunit of AP-1, or by manipulation of other factors, such as the AP-1 downstream target puc or the pnr transcription factor
Summary
Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems. Cell migration is an essential process in animal development, as well as in tissue repair It has been widely studied in model systems, where the focus has been largely on mechanosensation and mechanotransduction [1, 2]. In Drosophila development, cell migration has been studied in embryogenesis, in the process of dorsal closure [4, 5], and later on during metamorphosis, when many of the same genes are involved in thoracic closure [6]. This process involves cells everting from the wing imaginal discs, which spread over the preexisting larval epidermis [7].
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