title: Sirtuin-4 modulates sensitivity to induction of the mitochondrial permeability transition pore.
abstract: The sustained opening of the mitochondrial permeability transition pore (PTP) is a decisive event in the onset of irreversible cell injury. The PTP is modulated by numerous exogenous and endogenous effectors, including mitochondrial membrane potential, ions and metabolites. Mitochondrial sirtuins have recently emerged as pivotal mediators of mitochondrial metabolism. In the present study, we demonstrate that sirt-4 modulates sensitivity to PTP onset induced by calcium and the oxidative cross linking reagent phenylarsine oxide, and PTP dependent cytotoxicity brought about by TNF or doxorubicin. Moreover, the ability of sirt-4 to modulate onset of the PTP is dependent on the expression of glutamate dehydrogenase-1.
authors.affiliation: Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Verma
authors.forename: Nataly
authors.initials: N
authors.lastname: Shulga
authors.forename: John G
authors.initials: JG
authors.lastname: Pastorino
mesh_terms: D001152:Arsenicals / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D059008:Time-Lapse Imaging; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: D001152:Arsenicals; D003432:Cross-Linking Reagents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D014409:Tumor Necrosis Factor-alpha; C029341:oxophenylarsine; D004317:Doxorubicin; D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human; C525357:SIRT4 protein, human; D037761:Sirtuins; D005978:Glutathione; D002118:Calcium