Mitochondrial catalase overexpression protects insulin-producing cells against toxicity of reactive oxygen species and proinflammatory cytokines.
Insulin-producing cells are known for their extremely low antioxidant equipment with hydrogen peroxide (H(2)O(2))-inactivating enzymes. Therefore, catalase was stably overexpressed in mitochondria and for comparison in the cytoplasmic compartment of insulin-producing RINm5F cells and analyzed for its protective effect against toxicity of reactive oxygen species (ROS) and proinflammatory cytokines. Only mitochondrial overexpression of catalase provided protection against menadione toxicity, a chemical agent that preferentially generates superoxide radicals intramitochondrially. On the other hand, the cytoplasmic catalase overexpression provided better protection against H(2)O(2) toxicity. Mitochondrial catalase overexpression also preferentially protected against the toxicity of interleukin-1beta (IL-1beta) and a proinflammatory cytokine mixture (IL-1beta, tumor necrosis factor-alpha [TNF-alpha], and gamma-interferon [IFN-gamma]) that is more toxic than IL-1beta alone. Thus, it can be concluded that targeted overexpression of catalase in the mitochondria provides particularly effective protection against cell death in all situations in which ROS are generated intramitochondrially. The observed higher rate of cell death after exposure to a cytokine mixture in comparison with the weaker effect of IL-1beta alone may be due to an additive toxicity of TNF-alpha through ROS formation in mitochondria. The results emphasize the central role of mitochondrially generated ROS in the cytokine-mediated cell destruction of insulin-producing cells.
Institute of Clinical Biochemistry, Hannover Medical School, D-30623 Hannover, Germany.
Ewa
E
Gurgul
Stephan
S
Lortz
Markus
M
Tiedge
Anne
A
Jörns
Sigurd
S
Lenzen
D000818:Animals; D000933:Antifibrinolytic Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007328:Insulin / Q000378:metabolism; D007340:Insulinoma; D007371:Interferon-gamma / Q000633:toxicity; D007375:Interleukin-1 / Q000633:toxicity; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D008928:Mitochondria / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D016877:Oxidants / Q000633:toxicity; D010190:Pancreatic Neoplasms; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D024483:Vitamin K 3 / Q000633:toxicity
D000933:Antifibrinolytic Agents; D000970:Antineoplastic Agents; D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D016877:Oxidants; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D024483:Vitamin K 3; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D002374:Catalase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D005947:Glucose