Brain and liver mitochondria response to hyperthermia: changes in respiration system and enzymes activities

Abstract

Hyperthermia (HT) (40–43°C) in combination with chemotherapy or radiotherapy is used clinically for cancer treatment. HT increases effectiveness of chemotherapy in ovarian, colorectal, gastrointestinal and other cancers. It was believed that HT selectively kills cancer cells leaving healthy cells undamaged. However it appeared that different types of healthy tissue can be injured by HT as well, moreover their sensitivity to HT is different. More detailed knowledge about temperature effects in healthy tissues is needed in order to use HT treatment without damage of healthy tissues. We aimed to compare HT (40–47°C) effects on mitochondria (Mt) from healthy rat brain and liver tissues. For this purpose we compared Mt respiration with different substrates, and activity of respiratory system enzymes in rat liver and brain Mt. Under normothermic (37°C) conditions Mt respiration in states 2 and 3 with either 0.5 mM pyruvate + 0.5 mM malate (P+M) or 0.5 mM glutamate + 0.5 mM malate (G+M) and activities of enzymes (glutamate dehydrogenase (GDH) and complex I, but not pyruvate dehydrogenase (PDH) complex) were greater in liver Mt in comparison to brain Mt. Liver Mt were more sensitive to HT conditions – respiration in state 2 (V2 is indicator of inner mitochondria membrane permeability) in liver Mt increased at lower temperatures in comparison to brain Mt, oxidizing P+M and G+M. Changes induced in state 3 respiration (V3) also showed that liver Mt were more sensitive to HT – V3 notably decreased at 40–42°C in liver mitochondria oxidizing G+M or P+M, while in brain Mt state 3 respiration was stimulated by HT with P+M and inhibited only at 47°C temperature with G+M as substrate. Uncoupled respiration rate VCCCP with both substrates in brain Mt was not affected by HT, while in liver Mt VCCCP was inhibited in the temperature range 42–47°C. [...]