Mitochondrial Membrane Barrier Function as a Target of Hyperthermia

Abstract

Background and Objective. Hyperthermia is a promising modality for cancer treatment that urgently requires detailed knowledge on molecular and cellular processes for the rational development of treatment protocols. The thorough study of the response of the inner membrane of heart and liver mitochondria to hyperthermia was performed in order to establish the pattern of the hyperthermia-induced changes in the membrane barrier function. Material and Methods. The isolated mitochondria from rat heart and liver (of both genders) were used for experiments, as well as mitochondria isolated from the perfused male rat liver. Changes in the membrane permeability were evaluated by mitochondrial respiration in state 2 or by estimation of the modular kinetics of the membrane leak. Results. The inner membrane of isolated mitochondria from healthy tissues was found to be an extremely sensitive target of hyperthermia that exerted the response even in the febrile range. More severe hyperthermia compromised the inner mitochondrial membrane function; however, this response was tissue-specific and, to some extent, gender-dependent (for liver mitochondria). The data obtained by direct heating of isolated mitochondria were validated by experiments on the perfused liver. Conclusions. The obtained results imply a crucial importance of the evaluation of the tissue- and gender-specific differences while developing or improving the protocols for hyperthermic treatment or combinatory therapy.

Impact of Gender and Age on Hyperthermia-Induced Changes in Respiration of Liver Mitochondria

“…HT-induced progressive increase in V 2 was characteristic for all experimental groups indicating an increase in permeability of the inner membrane of liver mitochondria, supporting earlier reports by other authors [ 22 , 34 ]. A statistically significant increase in V 2 in P+M oxidizing mitochondria started at a lower temperature (40 °C) in males and females of older groups (3–4 and 6–7 months), while the uncoupling effect in mitochondria from 1–1.5 month age group became evident only at 42 °C.…”

“…Data on sexual dimorphism in oxidative capacity of liver mitochondria are somewhat controversial [ 17 , 18 , 19 , 20 , 21 ]. It has been reported that HT of 45–47 °C induces a stronger increase in the membrane permeability of liver mitochondria isolated from female rats than that of males [ 22 ]. In this study we aimed to examine gender-dependent aspects of mitochondrial response to HT in more detail, including estimating induced changes in mitochondrial respiration, ROS production, and the dependence of these processes on animal age.…”

Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines

“…93 cells could be based on temperature effects on membrane potential. Several studies in the past have shown that temperature could impact membrane barrier function in in isolated heart and liver mitochondria 31 , and in intact breast cancer cells 32 which also might explain the proton leak results. Furthermore, as explanation for the proton leak results could be find in potental increased expression of UCP2, which is often found characteristic feature of various tumors 33, 34 .…”

Uncoupling of oxidative phosphorylation and ATP synthase reversal within the hyperthermic heart

“…, ; Nauciene et al. ) have only used substrates that provide single entry of electrons in the ETS (CI substrates). In vivo the ETS allows a second input of electrons via CII which should be measured during in vitro mitochondrial assays to get a more representative measure of function, however an additional substrate with entry via the electron‐transferring flavoprotein was not tested in these experiments (Lemieux et al.…”

“…; Nauciene et al. ). It is therefore likely that the cardiovascular dysfunction associated with increasing hyperthermia may be due to a mismatch between energy supply and demand.…”