Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.

Lysosomes are terminal, degradative organelles of the endosomal pathway that undergo repeated fusion-fission cycles with themselves, endosomes, phagosomes, and autophagosomes. Lysosome number and size depends on balanced fusion and fission rates. Thus, conditions that favour fusion over fission can...

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Autores principales:	Golam T Saffi, Evan Tang, Sami Mamand, Subothan Inpanathan, Aaron Fountain, Leonardo Salmena, Roberto J Botelho
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2e13202baa35471ea147821ba54376ff
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spelling	oai:doaj.org-article:2e13202baa35471ea147821ba54376ff2021-12-02T20:16:12ZReactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.1932-620310.1371/journal.pone.0259313https://doaj.org/article/2e13202baa35471ea147821ba54376ff2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0259313https://doaj.org/toc/1932-6203Lysosomes are terminal, degradative organelles of the endosomal pathway that undergo repeated fusion-fission cycles with themselves, endosomes, phagosomes, and autophagosomes. Lysosome number and size depends on balanced fusion and fission rates. Thus, conditions that favour fusion over fission can reduce lysosome numbers while enlarging their size. Conversely, favouring fission over fusion may cause lysosome fragmentation and increase their numbers. PIKfyve is a phosphoinositide kinase that generates phosphatidylinositol-3,5-bisphosphate to modulate lysosomal functions. PIKfyve inhibition causes an increase in lysosome size and reduction in lysosome number, consistent with lysosome coalescence. This is thought to proceed through reduced lysosome reformation and/or fission after fusion with endosomes or other lysosomes. Previously, we observed that photo-damage during live-cell imaging prevented lysosome coalescence during PIKfyve inhibition. Thus, we postulated that lysosome fusion and/or fission dynamics are affected by reactive oxygen species (ROS). Here, we show that ROS generated by various independent mechanisms all impaired lysosome coalescence during PIKfyve inhibition and promoted lysosome fragmentation during PIKfyve re-activation. However, depending on the ROS species or mode of production, lysosome dynamics were affected distinctly. H2O2 impaired lysosome motility and reduced lysosome fusion with phagosomes, suggesting that H2O2 reduces lysosome fusogenecity. In comparison, inhibitors of oxidative phosphorylation, thiol groups, glutathione, or thioredoxin, did not impair lysosome motility but instead promoted clearance of actin puncta on lysosomes formed during PIKfyve inhibition. Additionally, actin depolymerizing agents prevented lysosome coalescence during PIKfyve inhibition. Thus, we discovered that ROS can generally prevent lysosome coalescence during PIKfyve inhibition using distinct mechanisms depending on the type of ROS.Golam T SaffiEvan TangSami MamandSubothan InpanathanAaron FountainLeonardo SalmenaRoberto J BotelhoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0259313 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Golam T Saffi Evan Tang Sami Mamand Subothan Inpanathan Aaron Fountain Leonardo Salmena Roberto J Botelho Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.
description	Lysosomes are terminal, degradative organelles of the endosomal pathway that undergo repeated fusion-fission cycles with themselves, endosomes, phagosomes, and autophagosomes. Lysosome number and size depends on balanced fusion and fission rates. Thus, conditions that favour fusion over fission can reduce lysosome numbers while enlarging their size. Conversely, favouring fission over fusion may cause lysosome fragmentation and increase their numbers. PIKfyve is a phosphoinositide kinase that generates phosphatidylinositol-3,5-bisphosphate to modulate lysosomal functions. PIKfyve inhibition causes an increase in lysosome size and reduction in lysosome number, consistent with lysosome coalescence. This is thought to proceed through reduced lysosome reformation and/or fission after fusion with endosomes or other lysosomes. Previously, we observed that photo-damage during live-cell imaging prevented lysosome coalescence during PIKfyve inhibition. Thus, we postulated that lysosome fusion and/or fission dynamics are affected by reactive oxygen species (ROS). Here, we show that ROS generated by various independent mechanisms all impaired lysosome coalescence during PIKfyve inhibition and promoted lysosome fragmentation during PIKfyve re-activation. However, depending on the ROS species or mode of production, lysosome dynamics were affected distinctly. H2O2 impaired lysosome motility and reduced lysosome fusion with phagosomes, suggesting that H2O2 reduces lysosome fusogenecity. In comparison, inhibitors of oxidative phosphorylation, thiol groups, glutathione, or thioredoxin, did not impair lysosome motility but instead promoted clearance of actin puncta on lysosomes formed during PIKfyve inhibition. Additionally, actin depolymerizing agents prevented lysosome coalescence during PIKfyve inhibition. Thus, we discovered that ROS can generally prevent lysosome coalescence during PIKfyve inhibition using distinct mechanisms depending on the type of ROS.
format	article
author	Golam T Saffi Evan Tang Sami Mamand Subothan Inpanathan Aaron Fountain Leonardo Salmena Roberto J Botelho
author_facet	Golam T Saffi Evan Tang Sami Mamand Subothan Inpanathan Aaron Fountain Leonardo Salmena Roberto J Botelho
author_sort	Golam T Saffi
title	Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.
title_short	Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.
title_full	Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.
title_fullStr	Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.
title_full_unstemmed	Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.
title_sort	reactive oxygen species prevent lysosome coalescence during pikfyve inhibition.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/2e13202baa35471ea147821ba54376ff
work_keys_str_mv	AT golamtsaffi reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition AT evantang reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition AT samimamand reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition AT subothaninpanathan reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition AT aaronfountain reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition AT leonardosalmena reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition AT robertojbotelho reactiveoxygenspeciespreventlysosomecoalescenceduringpikfyveinhibition
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Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition.

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