ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania major

Williams, R. A. M., Smith, T. K., Cull, B., Mottram, J. C. and Coombs, G. H. (2012) ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania major. PLoS Pathogens, 8(5), e1002695. (doi: 10.1371/journal.ppat.1002695)

Abstract

Macroautophagy has been shown to be important for the cellular remodelling required for Leishmania differentiation. We now demonstrate that L. major contains a functional ATG12-ATG5 conjugation system, which is required for ATG8-dependent autophagosome formation. Nascent autophagosomes were found commonly associated with the mitochondrion. L. major mutants lacking ATG5 (Δatg5) were viable as promastigotes but were unable to form autophagosomes, had morphological abnormalities including a much reduced flagellum, were less able to differentiate and had greatly reduced virulence to macrophages and mice. Analyses of the lipid metabolome of Δatg5 revealed marked elevation of phosphatidylethanolamines (PE) in comparison to wild type parasites. The Δatg5 mutants also had increased mitochondrial mass but reduced mitochondrial membrane potential and higher levels of reactive oxygen species. These findings indicate that the lack of ATG5 and autophagy leads to perturbation of the phospholipid balance in the mitochondrion, possibly through ablation of membrane use and conjugation of mitochondrial PE to ATG8 for autophagosome biogenesis, resulting in a dysfunctional mitochondrion with impaired oxidative ability and energy generation. The overall result of this is reduced virulence.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Williams, Mr Roderick and Cull, Mr Benjamin and Coombs, Professor Graham and Mottram, Professor Jeremy
• Authors: Williams, R. A. M., Smith, T. K., Cull, B., Mottram, J. C., and Coombs, G. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS Pathogens
• Publisher: Public Library of Science
• ISSN: 1553-7366
• ISSN (Online): 1553-7374
• Published Online: 17 May 2012
• Copyright Holders: Copyright © 2012 The Authors
• First Published: First published in PLoS Pathogens 8(5):e1002695
• Publisher Policy: Reproduced under a Creative Commons License

Related URLs

• PubMed

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
45414	1	Analysing the roles of petidases in Leishmania infectivity and pathogenicity	Jeremy Mottram	Medical Research Council (MRC)	G0700127	III - PARASITOLOGY