Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.
Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.
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DOI：
10.1371/journal.pgen.1004385
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
Trifunovic A
中科院分区：
文献类型：
--
作者：
Kukat A;Dogan SA;Edgar D;Mourier A;Jacoby C;Maiti P;Mauer J;Becker C;Senft K;Wibom R;Kudin AP;Hultenby K;Flögel U;Rosenkranz S;Ricquier D;Kunz WS;Trifunovic A
虽然线粒体功能障碍往往伴随着过量的活性氧（ROS）的产生，我们以前表明，随机体细胞mtDNA突变的增加不会导致氧化应激增加。正常水平的ROS和氧化应激也可能是主动代偿机制的结果，例如质子泄漏的轻度增加。解偶联蛋白2（UCP2）被认为在许多生理情况下发挥这样的作用。然而，我们发现UCP2在mtDNA突变小鼠中的上调与质子泄漏动力学或ROS产生的改变无关，这对目前关于UCP2在能量代谢中作用的观点提出了挑战。相反，我们的研究结果表明，高UCP2水平可以更好地利用脂肪酸氧化，从而对心脏中的线粒体功能产生有益影响，推迟全身性乳酸酸中毒，并延长这些小鼠的寿命。这项研究提出了一种新的机制，线粒体心肌病的适应性反应，在代谢的变化，改善呼吸链缺陷和更长的寿命。线粒体通过氧化磷酸化产生许多细胞功能所需的大部分能量。然而，这是以潜在有害的活性氧（ROS）的形式存在的，它可能会破坏各种生物大分子。通过轻度解偶联的线粒体膜电位的变化可以改变细胞中ROS的产生（“解偶联以存活”）。线粒体解偶联蛋白（UCPs）被认为在这一过程中发挥了核心作用。我们在mtDNA突变小鼠（一种早衰模型）中检测到UCP2含量增加。线粒体DNA突变小鼠中UCP2的消耗导致寿命进一步缩短，伴有线粒体心肌病的早期体征，伴有高系统性乳酸酸中毒，通常用作线粒体疾病的标志物。值得注意的是，我们的研究结果表明，UCP2的存在对呼吸缺陷线粒体产生有益的影响，而不影响ROS的产生或解偶联。相反，UCP2蛋白似乎介导了mtDNA突变心脏中检测到的脂肪酸代谢的有价值的上调。我们的研究结果提供了一种新的机制，线粒体的适应呼吸不足介导的UCP2，明确反对“解偶联生存”的理论。
Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan. Mitochondria produce the majority of the energy needed for numerous cell functions through oxidative phosphorylation. However, this comes with the cost in the form of potentially harmful reactive oxygen species (ROS) that could damage all kinds of biological macromolecules. Changes in mitochondrial membrane potential through mild uncoupling could alter ROS production in the cell (“uncoupling to survive”). Mitochondrial uncoupling proteins (UCPs) are believed to play a central role in this process. We detected increased amounts of UCP2 in mtDNA mutator mice, a model for premature aging. Depletion of UCP2 in mtDNA mutator mice led to further shortening of the lifespan with earlier signs of mitochondrial cardiomyopathy accompanied with high systemic lactic acidosis, often used as a marker of mitochondrial diseases. Remarkably, our results demonstrate that the presence of UCP2 wields beneficial effect on respiratory deficient mitochondria without affecting ROS production or uncoupling. Instead, UCP2 protein seems to mediate a valuable upregulation of fatty acid metabolism detected in mtDNA mutator hearts. Our results provide a novel mechanism of adaptation of mitochondria to respiratory deficiency mediated by UCP2 that clearly argues against the “uncoupling to survive” theory.
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DOI：
10.1196/annals.1293.023
发表时间：
2004-01-01
期刊：
MITOCHONDRIAL PATHOGENESIS: FROM GENES AND APOPTOSIS TO AGING AND DISEASE
影响因子：
--
作者：
DiMauro, S;Mancuso, M;Naini, A
通讯作者：
Naini, A
影响因子：
4.3
作者：
Jezek, P;Engstovà, H;Garlid, KD
通讯作者：
Garlid, KD
影响因子：
29
作者：
Ahlqvist, Kati J.;Hamalainen, Riikka H.;Suomalainen, Anu
通讯作者：
Suomalainen, Anu
影响因子：
3.5
作者：
Ogasawara, Emi;Nakada, Kazuto;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
影响因子：
29
作者：
Fridell, YWC;Sánchez-Blanco, A;Helfand, SL
通讯作者：
Helfand, SL