Abstract
Hypothermia provides an effective neuro and cardio-protection in clinical settings implying ischemia/reperfusion injury (I/R). At the onset of reperfusion, succinate-induced reactive oxygen species (ROS) production, impaired oxidative phosphorylation (OXPHOS), and decreased Ca2+ retention capacity (CRC) concur to mitochondrial damages. We explored the effects of temperature from 6 to 37 °C on OXPHOS, ROS production, and CRC, using isolated mitochondria from mouse brain and heart. Oxygen consumption and ROS production was gradually inhibited when cooling from 37 to 6 °C in brain mitochondria (BM) and heart mitochondria (HM). The decrease in ROS production was gradual in BM but steeper between 31 and 20 °C in HM. In respiring mitochondria, the gradual activation of complex II, in addition of complex I, dramatically enhanced ROS production at all temperatures without modifying respiration, likely because of ubiquinone over-reduction. Finally, CRC values were linearly increased by cooling in both BM and HM. In BM, the Ca2+ uptake rate by the mitochondrial calcium uniporter (MCU) decreased by 2.7-fold between 25 and 37 °C, but decreased by 5.7-fold between 25 and 37 °C in HM. In conclusion, mild cold (25–37 °C) exerts differential inhibitory effects by preventing ROS production, by reverse electron transfer (RET) in BM, and by reducing MCU-mediated Ca2+ uptake rate in BM and HM.
Highlights
Cold has been used for decades for neuroprotection and cardioprotection against ischemia-reperfusion injury [1–3]
The present study investigated the relationship between a range of temperatures (6, 10, 15, 20, 25, 31, and 37 ◦C) and several mitochondrial functions—namely, respiration, reactive oxygen species (ROS) production and Ca2+ retention capacity (CRC)—in brain and heart mitochondria isolated from wild-type mouse
To assess the influence of cold, isolated brain and heart mitochondria (BM and HM) oxygen consumption was measured at different temperatures from 37 to 6 ◦C with an interval of 5–6 ◦C
Summary
Cold has been used for decades for neuroprotection and cardioprotection against ischemia-reperfusion injury [1–3]. Chouchani et al have reported that succinate accumulation during ischemia could play a central role in this reperfusion ROS burst They proposed this latter was induced via the reverse electron transport (RET) towards complex I [7]. Over-reduced CoQ would create a bottleneck for electron, increasing electron leak through ROS production by Complex I All these mechanisms, in addition to the energetic fall during ischemia, concur to the mPTP opening that causes a massive release of Ca2+ contained inside mitochondria and can lead to cell death [9,10]. In addition to the energetic fall during ischemia, concur to the mPTP opening that causes a massive release of Ca2+ contained inside mitochondria and can lead to cell death [9,10] Studies exploring those functions according to temperature are scarce
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