Role of mitochondria in the immune response to cancer: a central role for Ca2+.
This study demonstrates that Ca2+ stimulates mitochondrial energy metabolism during spleen lymphocyte activation in response to the ascitic Walker 256 tumor in rats. Intracellular Ca2+ concentrations, phosphorylated protein kinase C (pPKC) levels, Bcl-2 protein contents, interleukin-2 (IL-2) levels, mitochondrial uncoupling protein-2 (UCP-2) contents and reactive oxygen species (ROS) were significantly elevated in these activated lymphocytes. Mitochondria of activated lymphocytes exhibited high free Ca2+ concentrations in the matrix and enhanced oligomycin-sensitive oxygen consumption, indicating an increased rate of oxidative phosphorylation. The production of ROS was largely decreased by diphenylene iodinium in the activated lymphocytes, suggesting that NADPH oxidase is the prevalent source of these species. Accumulation of UCP-2 and the anti-apoptotic protein Bcl-2 is probably important to prevent mitochondrial dysfunction and cell death elicited by the sustained high levels of intracellular Ca2+ and ROS and may explain the observed higher resistance from activated lymphocytes against the opening of the mitochondrial membrane permeability pore (MPT). All these changes were blocked by pretreatment of the rats with verapamil, an L-type Ca2+ channel antagonist. These data demonstrate a central role of Ca2+ in the control of mitochondrial bioenergetics in spleen lymphocytes during the immune response to cancer.
Degasperi
Giovanna R
GR
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-970, Brazil.
Velho
Jesus A
JA
Zecchin
Karina G
KG
Souza
Cláudio T
CT
Velloso
Lício A
LA
Borecký
Jiri
J
Castilho
Roger F
RF
Vercesi
Anibal E
AE
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002279:Carcinoma 256, Walker / Q000276:immunology*; D016923:Cell Death; D004734:Energy Metabolism; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism; D007473:Ion Channels; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D000071246:Uncoupling Protein 2
D007376:Interleukin-2; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D019255:NADPH Oxidases; D011493:Protein Kinase C; D002118:Calcium