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

Autor: Sanjiva Bimal, Chandra Shekhar Lal, Anjali Kumari, Vahab Ali, Ranjeet Kumar Paswan, Pradeep Das, Preeti Sinha, Krishn Pratap Singh, Abhishek Mandal
Rok vydání: 2017
Předmět:
0301 basic medicine
Cytoplasm
Leishmania Donovani
Life Cycles
Cell Membranes
lcsh:Medicine
Apoptosis
Protozoology
White Blood Cells
Animal Cells
Medicine and Health Sciences
lcsh:Science
Protozoans
Leishmania
chemistry.chemical_classification
Multidisciplinary
Cell Death
biology
Mitochondria
Cell biology
Zinc
Chemistry
Cell Processes
Physical Sciences
Leishmaniasis
Visceral
DNA fragmentation
Protozoan Life Cycles
Cellular Types
Cellular Structures and Organelles
Intracellular
Research Article
Chemical Elements
Programmed cell death
Immune Cells
Immunology
030106 microbiology
Leishmania donovani
Microbiology
Host-Parasite Interactions
03 medical and health sciences
Parasitic Diseases
Animals
Humans
Reactive oxygen species
Blood Cells
Cell growth
Promastigotes
Macrophages
Intracellular parasite
lcsh:R
Organisms
Biology and Life Sciences
Cell Biology
Intracellular Membranes
biology.organism_classification
Parasitic Protozoans
030104 developmental biology
chemistry
lcsh:Q
Reactive Oxygen Species
Developmental Biology
Zdroj: PLoS ONE, Vol 12, Iss 6, p e0178800 (2017)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0178800
Popis: 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 (ZnSO4). Treatment of parasites with TPEN rather than ZnSO4 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.
Databáze: OpenAIRE
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