Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2.
Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2.
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DOI：
10.1371/journal.pgen.1004063
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Rongo C
中科院分区：
文献类型：
--
作者：
Ghose P;Park EC;Tabakin A;Salazar-Vasquez N;Rongo C
许多需氧生物遇到缺氧环境，因此必须有适应机制才能在这种压力下生存。重要的是要了解线粒体如何对缺氧作出反应，因为它们在利用氧气产生细胞能量方面发挥着关键作用。在这里，我们研究线粒体应激反应，在C。线虫，它们通过进入运动停止的可逆假死状态来适应极端缺氧（缺氧，少于0.1%的氧气）。我们发现，神经元线粒体进行DRP-1依赖性的分裂缺氧反应，并进行再灌注后复氧。缺氧反应途径，包括EGL-9和HIF-1，不需要缺氧诱导的分裂，但在复氧过程中调节线粒体重建。egl-9的突变体表现出线粒体的快速再融合和在复氧过程中从假死中快速恢复的行为;这两种表型都需要HIF-1。线粒体显着更大的egl-9突变体复氧后，表型类似于应激诱导的线粒体过度融合（SIMH）。缺氧导致线粒体氧化应激，并且氧化反应因子SKN-1/Nrf是在复氧期间快速线粒体再融合和快速行为恢复所需的。作为对缺氧的响应，SKN-1促进线粒体驻留蛋白Stomatin-like 1（STL-1）的表达，这有助于促进缺氧后的线粒体动力学。我们的研究结果表明，存在一个保守的缺氧应激反应，涉及线粒体分裂和融合的变化。缺氧在心脏病发作、缺血性中风和创伤性损伤等多种人类疾病中发挥作用。需氧生物利用氧在线粒体中产生细胞能量;因此，缺氧导致能量耗尽。低氧可能是灾难性的组织，如神经系统，其中有高能量需求和糖酵解储备少。相比之下，其他细胞，包括干细胞和肿瘤内的癌细胞，在低氧环境中适应和茁壮成长。我们刚刚开始了解不同的生物体，甚至同一生物体中的不同细胞类型如何对低氧条件做出反应。考虑到线粒体在有氧能量产生中的作用，线粒体对缺氧的反应特别关键。此外，线粒体在缺氧期间通过产生活性氧、破坏钙稳态和激活细胞死亡途径来主动损伤细胞。在这里，我们使用遗传学的方法来表明，线粒体进行裂变期间缺氧和氧恢复后的再融合。缺氧反应途径和氧化应激反应途径共同调节这种反应。我们发现了一种新的因子，即造口素样蛋白，作为响应缺氧应激的线粒体融合的启动子。我们的发现揭示了一种新的机制--调节线粒体动力学--细胞通过这种机制来适应缺氧应激。
Many aerobic organisms encounter oxygen-deprived environments and thus must have adaptive mechanisms to survive such stress. It is important to understand how mitochondria respond to oxygen deprivation given the critical role they play in using oxygen to generate cellular energy. Here we examine mitochondrial stress response in C. elegans, which adapt to extreme oxygen deprivation (anoxia, less than 0.1% oxygen) by entering into a reversible suspended animation state of locomotory arrest. We show that neuronal mitochondria undergo DRP-1-dependent fission in response to anoxia and undergo refusion upon reoxygenation. The hypoxia response pathway, including EGL-9 and HIF-1, is not required for anoxia-induced fission, but does regulate mitochondrial reconstitution during reoxygenation. Mutants for egl-9 exhibit a rapid refusion of mitochondria and a rapid behavioral recovery from suspended animation during reoxygenation; both phenotypes require HIF-1. Mitochondria are significantly larger in egl-9 mutants after reoxygenation, a phenotype similar to stress-induced mitochondria hyperfusion (SIMH). Anoxia results in mitochondrial oxidative stress, and the oxidative response factor SKN-1/Nrf is required for both rapid mitochondrial refusion and rapid behavioral recovery during reoxygenation. In response to anoxia, SKN-1 promotes the expression of the mitochondrial resident protein Stomatin-like 1 (STL-1), which helps facilitate mitochondrial dynamics following anoxia. Our results suggest the existence of a conserved anoxic stress response involving changes in mitochondrial fission and fusion. Oxygen deprivation plays a role in multiple human diseases ranging from heart attack, ischemic stroke, and traumatic injury. Aerobic organisms use oxygen to generate cellular energy in mitochondria; thus, oxygen deprivation results in energy depletion. Low oxygen can be catastrophic in tissues like the nervous system, which has high-energy demands and few glycolytic reserves. By contrast, other cells, including stem cells and cancerous cells within tumors, adapt and thrive in low oxygen. We are just beginning to understand how different organisms and even different cell types within the same organism respond to low oxygen conditions. The response of mitochondria to oxygen deprivation is particularly critical given their role in aerobic energy production. In addition, mitochondria actively injure cells during oxygen deprivation through the generation of reactive oxygen species, the disruption of calcium homeostasis, and the activation of cell death pathways. Here we use a genetic approach to show that mitochondria undergo fission during oxygen deprivation and refusion upon oxygen restoration. The hypoxia response pathway and the oxidative stress response pathway together modulate this response. We identify a new factor, stomatin-like protein, as a promoter of mitochondrial fusion in response to oxygen deprivation stress. Our findings uncover a new mechanism – regulated mitochondrial dynamics – by which cells adapt to oxygen deprivation stress.
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影响因子：
2.7
作者：
Collins, Tony J.
通讯作者：
Collins, Tony J.
DOI：
10.1073/pnas.96.26.15202
发表时间：
1999-12-21
影响因子：
11.1
作者：
Darby, C;Cosma, CL;Manoil, C
通讯作者：
Manoil, C
影响因子：
4.8
作者：
Cocheme, Helena M.;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
4.8
作者：
Hanson, GT;Aggeler, R;Remington, SJ
通讯作者：
Remington, SJ
影响因子：
56.9
作者：
Bruick, RK;McKnight, SL
通讯作者：
McKnight, SL