Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells.
Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.
Raza
Haider
H
Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, POBox 17666, Al Ain, United Arab Emirates. h.raza@uaeu.ac.ae <h.raza@uaeu.ac.ae>
John
Annie
A
Brown
Eric M
EM
Benedict
Sheela
S
Kambal
Amr
A
D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D016877:Oxidants; D019392:Cytochrome P-450 CYP2E1; D013482:Superoxide Dismutase; D005978:Glutathione; D003474:Curcumin; D008550:Melatonin; C027576:4-hydroxy-2-nonenal