Role of mitochondria in the immune response to cancer: a central role for Ca super(2+)

• Published in: Journal of bioenergetics and biomembranes 2006-02, Vol.38 (1), p.1-10
• Main Authors: Degasperi, Giovanna R, Velho, Jesus A, Zecchin, Karina G, Souza, Claudio T, Velloso, Licio A, Borecky, Jiri, Castilho, Roger F, Vercesi, Anibal E
• Format: Article
• Language: English
• ISSN: 0145-479X
• DOI: 10.1007/s10863-006-9000-y

This study demonstrates that Ca super(2+) stimulates mitochondrial energy metabolism during spleen lymphocyte activation in response to the ascitic Walker 256 tumor in rats. Intracellular Ca super(2+) 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 Ca super(2+) 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 Ca super(2+) 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 Ca super(2+) channel antagonist. These data demonstrate a central role of Ca super(2+) in the control of mitochondrial bioenergetics in spleen lymphocytes during the immune response to cancer.