Ischemic damage to every segment of the oxidative phosphorylation cascade elevates ETC driving force and ROS production in cardiac mitochondria.
Ischemic damage to every segment of the oxidative phosphorylation cascade elevates ETC driving force and ROS production in cardiac mitochondria.
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DOI：
10.1152/ajpheart.00129.2022
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发表时间：
2022-09-01
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影响因子：
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心肌缺血对心肌细胞线粒体 ATP 产生具有长期的负面影响。然而，导致线粒体功能改变的氧化磷酸化途径受损的位置尚不清楚。缺血后线粒体活性氧（ROS）的产生增加，但控制这种增加的具体因素尚不清楚。为了确定缺血如何影响线粒体能量转换级联和 ROS 产生，在 60 分钟的控制流（对照）或无流缺血（缺血）后，测量从大鼠心脏分离的线粒体在静息、中间和最大呼吸速率下的线粒体驱动力 [氧化还原电位和膜电位 (ΔΨ)]。使用驱动力和通量计算脱氢酶、电子传递链 (ETC) 以及 ATP 合成和运输的有效活性。缺血降低了最大线粒体呼吸速率，并降低了呼吸对氧化还原电位和 ΔΨ 的反应性。缺血会降低氧化磷酸化途径各个组成部分的活性：脱氢酶、ETC 以及 ATP 合成和运输。 ROS 的产生与 ETC 的驱动力呈线性相关；然而，缺血线粒体表现出更大的驱动力降低 ETC 和更高的 ROS 产生。总体而言，结果表明缺血普遍损害氧化磷酸化途径，降低线粒体对驱动力的敏感性，并增加电子从 ETC 泄漏的倾向。这些发现强调，改善缺血后线粒体功能的策略必须针对整个线粒体能量转换级联。新颖且值得注意的这项综合分析首次评估了心肌缺血如何改变线粒体驱动力，以及线粒体能量转导途径的各个片段对缺血后功能减弱的影响程度。这项研究表明，缺血后活性氧产生的增加与电子传递链有效活性的降低和电子传递链下游驱动力的增大有关。
Myocardial ischemia has long-lasting negative impacts on cardiomyocyte mitochondrial ATP production. However, the location(s) of damage to the oxidative phosphorylation pathway responsible for altered mitochondrial function is unclear. Mitochondrial reactive oxygen species (ROS) production increases following ischemia, but the specific factors controlling this increase are unknown. To determine how ischemia affects the mitochondrial energy conversion cascade and ROS production, mitochondrial driving forces [redox potential and membrane potential (ΔΨ)] were measured at resting, intermediate, and maximal respiration rates in mitochondria isolated from rat hearts after 60 min of control flow (control) or no-flow ischemia (ischemia). The effective activities of the dehydrogenase enzymes, the electron transport chain (ETC), and ATP synthesis and transport were computed using the driving forces and flux. Ischemia lowered maximal mitochondrial respiration rates and diminished the responsiveness of respiration to both redox potential and ΔΨ. Ischemia decreased the activities of every component of the oxidative phosphorylation pathway: the dehydrogenase enzymes, the ETC, and ATP synthesis and transport. ROS production was linearly related to driving force down the ETC; however, ischemia mitochondria demonstrated a greater driving force down the ETC and higher ROS production. Overall, results indicate that ischemia ubiquitously damages the oxidative phosphorylation pathway, reduces mitochondrial sensitivity to driving forces, and augments the propensity for electrons to leak from the ETC. These findings underscore that strategies to improve mitochondrial function following ischemia must target the entire mitochondrial energy conversion cascade. NEW & NOTEWORTHY This integrative analysis is the first to assess how myocardial ischemia alters the mitochondrial driving forces and the degree to which individual segments of the mitochondrial energy transduction pathway contribute to diminished function following ischemia. This investigation demonstrates that increased reactive oxygen species production following ischemia is related to a lower effective activity of the electron transport chain and a greater driving force down the electron transport chain.
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DOI：
10.1124/jpet.105.091702
发表时间：
2006-01-01
影响因子：
3.5
作者：
Chen, Q;Hoppel, CL;Lesnefsky, EJ
通讯作者：
Lesnefsky, EJ
影响因子：
2.9
作者：
Glancy, Brian;Willis, Wayne T.;Balaban, Robert S.
通讯作者：
Balaban, Robert S.
影响因子：
5
作者：
Borutaite, V;Morkuniene, R;Brown, GC
通讯作者：
Brown, GC
影响因子：
8.8
作者：
Fisher-Wellman KH;Davidson MT;Narowski TM;Lin CT;Koves TR;Muoio DM
通讯作者：
Muoio DM
影响因子：
5
作者：
Arieli, Y;Gursahani, H;Schaefer, S
通讯作者：
Schaefer, S