Cargando…

Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani

Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alterna...

Descripción completa

Detalles Bibliográficos
Autores principales: Kumari, Anjali, Singh, Krishn Pratap, Mandal, Abhishek, Paswan, Ranjeet Kumar, Sinha, Preeti, Das, Pradeep, Ali, Vahab, Bimal, Sanjiva, Lal, Chandra Shekhar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460814/
https://www.ncbi.nlm.nih.gov/pubmed/28586364
http://dx.doi.org/10.1371/journal.pone.0178800
_version_ 1783242236649013248
author Kumari, Anjali
Singh, Krishn Pratap
Mandal, Abhishek
Paswan, Ranjeet Kumar
Sinha, Preeti
Das, Pradeep
Ali, Vahab
Bimal, Sanjiva
Lal, Chandra Shekhar
author_facet Kumari, Anjali
Singh, Krishn Pratap
Mandal, Abhishek
Paswan, Ranjeet Kumar
Sinha, Preeti
Das, Pradeep
Ali, Vahab
Bimal, Sanjiva
Lal, Chandra Shekhar
author_sort Kumari, Anjali
collection PubMed
description Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alternates between sand fly and human host. To survive and establish infections, Leishmania parasites scavenge and internalize nutrients from the host. Nevertheless, host cells presents mechanism like nutrient restriction to inhibit microbial growth and control infection. Zinc is crucial for cellular growth and disruption in its homeostasis hinders growth and survival in many cells. However, little is known about the role of zinc in Leishmania growth and survival. In this study, the effect of zinc on the growth and survival of L.donovani was analyzed by both Zinc-depletion and Zinc-supplementation using Zinc-specific chelator N, N, N', N'–tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) and Zinc Sulfate (ZnSO(4)). Treatment of parasites with TPEN rather than ZnSO(4) had significantly affected the growth in a dose- and time-dependent manner. The pre-treatment of promastigotes with TPEN resulted into reduced host-parasite interaction as indicated by decreased association index. Zn depletion resulted into flux in intracellular labile Zn pool and increased in ROS generation correlated with decreased intracellular total thiol and retention of plasma membrane integrity without phosphatidylserine exposure in TPEN treated promastigotes. We also observed that TPEN-induced Zn depletion resulted into collapse of mitochondrial membrane potential which is associated with increase in cytosolic calcium and cytochrome-c. DNA fragmentation analysis showed increased DNA fragments in Zn-depleted cells. In summary, intracellular Zn depletion in the L. donovani promastigotes led to ROS-mediated caspase-independent mitochondrial dysfunction resulting into apoptosis-like cell death. Therefore, cellular zinc homeostasis in Leishmania can be explored for new drug targets and chemotherapeutics to control Leishmanial growth and disease progression.
format Online
Article
Text
id pubmed-5460814
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-54608142017-06-15 Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani Kumari, Anjali Singh, Krishn Pratap Mandal, Abhishek Paswan, Ranjeet Kumar Sinha, Preeti Das, Pradeep Ali, Vahab Bimal, Sanjiva Lal, Chandra Shekhar PLoS One Research Article Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alternates between sand fly and human host. To survive and establish infections, Leishmania parasites scavenge and internalize nutrients from the host. Nevertheless, host cells presents mechanism like nutrient restriction to inhibit microbial growth and control infection. Zinc is crucial for cellular growth and disruption in its homeostasis hinders growth and survival in many cells. However, little is known about the role of zinc in Leishmania growth and survival. In this study, the effect of zinc on the growth and survival of L.donovani was analyzed by both Zinc-depletion and Zinc-supplementation using Zinc-specific chelator N, N, N', N'–tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) and Zinc Sulfate (ZnSO(4)). Treatment of parasites with TPEN rather than ZnSO(4) had significantly affected the growth in a dose- and time-dependent manner. The pre-treatment of promastigotes with TPEN resulted into reduced host-parasite interaction as indicated by decreased association index. Zn depletion resulted into flux in intracellular labile Zn pool and increased in ROS generation correlated with decreased intracellular total thiol and retention of plasma membrane integrity without phosphatidylserine exposure in TPEN treated promastigotes. We also observed that TPEN-induced Zn depletion resulted into collapse of mitochondrial membrane potential which is associated with increase in cytosolic calcium and cytochrome-c. DNA fragmentation analysis showed increased DNA fragments in Zn-depleted cells. In summary, intracellular Zn depletion in the L. donovani promastigotes led to ROS-mediated caspase-independent mitochondrial dysfunction resulting into apoptosis-like cell death. Therefore, cellular zinc homeostasis in Leishmania can be explored for new drug targets and chemotherapeutics to control Leishmanial growth and disease progression. Public Library of Science 2017-06-06 /pmc/articles/PMC5460814/ /pubmed/28586364 http://dx.doi.org/10.1371/journal.pone.0178800 Text en © 2017 Kumari et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kumari, Anjali
Singh, Krishn Pratap
Mandal, Abhishek
Paswan, Ranjeet Kumar
Sinha, Preeti
Das, Pradeep
Ali, Vahab
Bimal, Sanjiva
Lal, Chandra Shekhar
Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani
title Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani
title_full Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani
title_fullStr Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani
title_full_unstemmed Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani
title_short Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani
title_sort intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in leishmania donovani
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460814/
https://www.ncbi.nlm.nih.gov/pubmed/28586364
http://dx.doi.org/10.1371/journal.pone.0178800
work_keys_str_mv AT kumarianjali intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT singhkrishnpratap intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT mandalabhishek intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT paswanranjeetkumar intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT sinhapreeti intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT daspradeep intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT alivahab intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT bimalsanjiva intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani
AT lalchandrashekhar intracellularzincfluxcausesreactiveoxygenspeciesmediatedmitochondrialdysfunctionleadingtocelldeathinleishmaniadonovani