Overexpression of proline oxidase induces proline-dependent and mitochondria-mediated apoptosis |
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Authors: | Chien-an A Hu Steven P Donald Jian Yu Wei-Wen Lin Zhihe Liu Gary Steel Cassandra Obie David Valle James M Phang |
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Institution: | (1) Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima 770-8503, Japan;(2) Department of Laboratory Medicine, School of Medicine, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima 770-8503, Japan;(3) Department of Gastroenterology, Affiliated Hospital, Nantong Medical College, Nantong, 226001, China |
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Abstract: | The neuropathogenesis of influenza-associated encephalopathy in children and Reye's syndrome remains unclear. A surveillance
effort conducted during 2000-2003 in South-West Japan reveals that almost all fatal and handicapped influenza-associated encephalopathy
patients exhibit a disorder of mitochondrial β-oxidation with elevated serum acylcarnitine ratios (C16:0+C18:1)/C2. Here we show invasion by a non-neurotropic epidemic influenza A H3N2 virus in cerebral capillaries with progressive brain
edema after intranasal infection of mice having impaired mitochondrial β-oxidation congenitally or posteriorly in the newborn/
suckling periods. Mice genetically lacking of carnitine transporter OCTN2, resulting in carnitine deficiency and impaired
β-oxidation, exhibited significant higher virus-genome numbers in the brain, accumulation of virus antigen exclusively in
the cerebral capillaries and increased brain vascular permeability compared to in wild type mice. Mini-plasmin, which proteolytically
potentiates influenza virus multiplication in vivo and destroys the blood-brain barrier, accumulated with virus antigen in the brain capillaries of OCTN2-deficient mice but
only a little in wild-type mice. These results suggest that the impaired mitochondrial β-oxidation changes the susceptibility
to a non-neurotropic influenza A virus as to multiplication in the brain capillaries and to cause brain edema. These pathological
findings in the brain of mice having impaired mitochondrial β-oxidation after influenza virus infection may have implications
for human influenza-associated encephalopathy. |
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Keywords: | β -oxidation carnitine deficiency fatty acid metabolism influenza-associated encephalopathy influenza virus mini-plasmin |
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