A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

English version

Autoři: Daniel C. Maddison ^aff001; Mónica Alfonso-Núñez ^aff001; Aisha M. Swaih ^aff001; Carlo Breda ^aff001; Susanna Campesan ^aff001; Natalie Allcock ^aff003; Anna Straatman-Iwanowska ^aff003; Charalambos P. Kyriacou ^aff001; Flaviano Giorgini ^aff001
Působiště autorů: Department of Genetics and Genome Biology, University of Leicester, Leicester, LE1 7RH, United Kingdom ^aff001; Leicester School of Allied Health Sciences, Faculty of Health and Life Sciences, De Montfort University, Leicester, LE1 9BH, United Kingdom ^aff002; Core Biotechnology Services, Adrian Building, University of Leicester, University Road, Leicester, LE1 7RH, Leicestershire, United Kingdom ^aff003
Vyšlo v časopise: A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics. PLoS Genet 16(11): e1009129. doi:10.1371/journal.pgen.1009129
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009129

Souhrn

The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson’s disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway.

Klíčová slova:

293T cells – Climbing – Drosophila melanogaster – Hyperexpression techniques – Mitochondria – Phenotypes – Phosphorylation – RNA interference

Zdroje

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