Malarial infection develops mitochondrial pathology and mitochondrial oxidative stress to promote hepatocyte apoptosis

Dey, Sumanta ; Guha, Mithu ; Alam, Athar ; Goyal, Manish ; Bindu, Samik ; Pal, Chinmay ; Maity, Pallab ; Mitra, Kalyan ; Bandyopadhyay, Uday (2009) Malarial infection develops mitochondrial pathology and mitochondrial oxidative stress to promote hepatocyte apoptosis Free Radical Biology and Medicine, 46 (2). pp. 271-281. ISSN 0891-5849

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Activation of the mitochondrial apoptosis pathway by oxidative stress has been implicated in hepatocyte apoptosis during malaria. Because mitochondria are the source and target of reactive oxygen species (ROS), we have investigated whether hepatocyte apoptosis is linked to mitochondrial pathology and mitochondrial ROS generation during malaria. Malarial infection induces mitochondrial pathology by inhibiting mitochondrial respiration, dehydrogenases, and transmembrane potential and damaging the ultrastructure as evident from transmission electron microscopic studies. Mitochondrial GSH depletion and formation of protein carbonyl indicate that mitochondrial pathology is associated with mitochondrial oxidative stress. Fluorescence imaging of hepatocytes documents intramitochondrial superoxide anion (O2·−) generation during malaria. O2·− inactivates mitochondrial aconitase to release iron from iron–sulfur clusters, which forms the hydroxyl radical (radical dotOH) interacting with H2O2 produced concurrently. Malarial infection inactivates mitochondrial aconitase, and carbonylation of aconitase is evident from Western immunoblotting. The release of iron has been documented by fluorescence imaging of hepatocytes using Phen Green SK, and mitochondrial radical dotOH generation has been confirmed. During malaria, the depletion of cardiolipin and formation of the mitochondrial permeability transition pore favor cytochrome c release to activate caspase-9. Interestingly, mitochondrial radical dotOH generation correlates with the activation of both caspase-9 and caspase-3 with the progress of malarial infection, indicating the critical role of ·OH.

Item Type:Article
Source:Copyright of this article belongs to Society for Free Radical Biology and Medicine.
Keywords:Malaria; Apoptosis; Reactive Oxygen Species; Mitochondria; Liver Damage; Free Radicals
ID Code:98502
Deposited On:20 Aug 2014 08:58
Last Modified:20 Aug 2014 10:00

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