Munns Shane E, Lui James K C, Arthur Peter G
School of Biomedical & Chemical Sciences, M310, University of Western Australia, Crawley, WA 6009, Australia.
Free Radic Biol Med. 2005 Jun 15;38(12):1594-603. doi: 10.1016/j.freeradbiomed.2005.02.028. Epub 2005 Mar 19.
Metabolic responses of mammalian cells toward declining oxygen concentration are generally thought to occur when oxygen limits mitochondrial ATP production. However, at oxygen concentrations markedly above those limiting to mitochondria, several mammalian cell types display reduced rates of oxygen consumption without energy stress or compensatory increases in glycolytic ATP production. We used mammalian Jurkat T cells as a model system to identify mechanisms responsible for these changes in metabolic rate. Oxygen consumption was 31% greater at high oxygen (150-200 microM) compared to low oxygen (5-10 microM). Hydrogen peroxide was implicated in the response as catalase prevented the increase in oxygen consumption normally associated with high oxygen. Cell-derived hydrogen peroxide, predominately from the mitochondria, was elevated with high oxygen. Oxygen consumption related to intracellular calcium turnover was shown, through EDTA chelation and dantrolene antagonism of the ryanodine receptor, to account for 70% of the response. Oligomycin inhibition of oxygen consumption indicated that mitochondrial proton leak was also sensitive to changes in oxygen concentration. Our results point toward a mechanism in which changes in oxygen concentration influence the rate of hydrogen peroxide production by mitochondria, which, in turn, alters cellular ATP use associated with intracellular calcium turnover and energy wastage through mitochondrial proton leak.
哺乳动物细胞对氧浓度下降的代谢反应通常被认为是在氧限制线粒体ATP产生时发生的。然而，在氧浓度明显高于限制线粒体的浓度时，几种哺乳动物细胞类型显示出氧消耗速率降低，且没有能量应激或糖酵解ATP产生的代偿性增加。我们使用哺乳动物Jurkat T细胞作为模型系统来确定导致这些代谢率变化的机制。与低氧（5-10微摩尔）相比，高氧（150-200微摩尔）时的氧消耗高出31%。过氧化氢与该反应有关，因为过氧化氢酶可阻止通常与高氧相关的氧消耗增加。细胞衍生的过氧化氢主要来自线粒体，在高氧时会升高。通过EDTA螯合和ryanodine受体的丹曲林拮抗作用表明，与细胞内钙周转相关的氧消耗占该反应的70%。寡霉素对氧消耗的抑制表明线粒体质子泄漏也对氧浓度变化敏感。我们的结果指向一种机制，即氧浓度的变化影响线粒体产生过氧化氢的速率，进而改变与细胞内钙周转相关的细胞ATP利用以及通过线粒体质子泄漏造成的能量浪费。
