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  • Title: Effects of copper and temperature on heart mitochondrial hydrogen peroxide production.
    Author: Isei MO, Kamunde C.
    Journal: Free Radic Biol Med; 2020 Feb 01; 147():114-128. PubMed ID: 31825803.
    Abstract:
    High energy demand for continuous mechanical work and large number of mitochondria predispose the heart to excessive reactive oxygen species (ROS) production that may precipitate oxidative stress and heart failure. While mitochondria have been proposed as a unifying cellular target and driver of adverse effects induced by diverse stressful states, there is limited understanding of how heart mitochondrial ROS homeostasis is affected by combinations of stress factors. Thus, we probed the effect of copper (Cu) and thermal stress on ROS (as hydrogen peroxide, H2O2) emission and elucidated the effects of Cu on ROS production sites in rainbow trout heart mitochondria using the Amplex UltraRed-horseradish peroxidase detection system optimized for our model. Mitochondria oxidizing malate-glutamate or succinate were incubated at 4, 11 (control) and 23 °C and exposed to a range (1-100 μM) of Cu concentrations. We found that the rates and patterns of H2O2 emission depended on substrate type, Cu concentration and temperature. In mitochondria oxidizing malate-glutamate, Cu increased the rate of H2O2 emission with a spike at 1 μM while temperature had no effect. In contrast, both temperature and Cu increased the rate of H2O2 emission in mitochondria oxidizing succinate with a prominent spike at 25 μM Cu. The rates of H2O2 emission at the three temperatures during the spike imposed by 25 μM Cu were of the order 11 > 23 > 4 °C. Interestingly, 5 μM Cu supressed H2O2 emission in mitochondria oxidizing succinate or malate-glutamate suggesting a common mechanism of action independent of substrate type. In the absence of Cu, the site-specific capacities of H2O2 emission were: complex III outer ubiquinone binding site (site IIIQo) > complex II flavin site (site IIF) ≥ complex I flavin site (site IF) > complex I ubiquinone-binding site (site IQ). Rotenone marginally increased succinate-driven H2O2 emission suggesting either the absence of reverse electron transport (RET)-driven ROS production at site IQ or masking of the expected rotenone response (reduction) by H2O2 produced from other sites. Cu acted at multiple sites in the electron transport system resulting in different site-specific H2O2 emission responses depending on the concentration. Specifically, site IF H2O2 emission was suppressed by Cu concentration-dependently while H2O2 emission by site IIF was inhibited and stimulated by low and high concentrations of Cu, respectively. Additionally, emission from site IIIQo was stimulated by low and inhibited by high Cu concentrations. Overall, our study unveiled distinctive effects and sites of modulation of mitochondrial ROS production by Cu with implications for cardiac redox signaling networks and development of mitochondria-targeted Cu-based drugs.
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