Malarial infection develops mitochondrial pathology and mitochondrial oxidative stress to promote hepatocyte apoptosis.
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 (O(2)(-)) generation during malaria. O(2)(-) inactivates mitochondrial aconitase to release iron from iron-sulfur clusters, which forms the hydroxyl radical ((.)OH) interacting with H(2)O(2) 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 (.)OH 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 (.)OH generation correlates with the activation of both caspase-9 and caspase-3 with the progress of malarial infection, indicating the critical role of (.)OH.
Dey
Sumanta
S
Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
Guha
Mithu
M
Alam
Athar
A
Goyal
Manish
M
Bindu
Samik
S
Pal
Chinmay
C
Maity
Pallab
P
Mitra
Kalyan
K
Bandyopadhyay
Uday
U
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002308:Cardiolipins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology* / Q000648:ultrastructure; D007501:Iron / Q000032:analysis; D008099:Liver / Q000648:ultrastructure; D008288:Malaria / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D018512:Parasitemia; D010967:Plasmodium yoelii / Q000254:growth & development / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000032:analysis; D000099156:Superoxide Dismutase 2
D000154:Aconitate Hydratase; D002308:Cardiolipins; D053148:Caspase 3; D053453:Caspase 9; D007501:Iron; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2