Huang Wen-Yi, Jou Mei-Jie, Peng Tsung-I
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan.
Department of Physiology and Pharmacology, and Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
Free Radic Biol Med. 2014 Feb;67:314-29. doi: 10.1016/j.freeradbiomed.2013.11.019. Epub 2013 Nov 27.
Transient opening of the mitochondrial permeability transition pore plays a crucial role in hypoxic preconditioning-induced protection. Recently, the cyclophilin-D component of the mitochondrial permeability transition pore has been shown to interact with and regulate the F1F0-ATP synthase. However, the precise role of the F1F0-ATP synthase and the interaction between cyclophilin-D and F1F0-ATP synthase in the mitochondrial permeability transition pore and hypoxic preconditioning remain uncertain. Here we found that a 1-h hypoxic preconditioning delayed apoptosis and improved cell survival after stimulation with various apoptotic inducers including H2O2, ionomycin, and arachidonic acid in mitochondrial DNA T8993G mutation (NARP) osteosarcoma 143B cybrids, an F1F0-ATP synthase defect cell model. This hypoxic preconditioning protected NARP cybrid cells against focal laser irradiation-induced oxidative stress by suppressing reactive oxygen species formation and preventing the depletion of cardiolipin. Furthermore, the protective functions of transient opening of the mitochondrial permeability transition pore in both NARP cybrids and wild-type 143B cells can be augmented by hypoxic preconditioning. Disruption of the interaction between cyclophilin-D and F1F0-ATP synthase by cyclosporin A attenuated the mitochondrial protection induced by hypoxic preconditioning in both NARP cybrids and wild-type 143B cells. Our results demonstrate that the interaction between cyclophilin-D and F1F0-ATP synthase is important in the hypoxic preconditioning-induced cell protection. This finding improves our understanding of the mechanism of mitochondrial permeability transition pore opening in cells in response to hypoxic preconditioning, and will be helpful in further developing new pharmacological agents targeting hypoxia-reoxygenation injury and mitochondria-mediated cell death.
线粒体通透性转换孔的短暂开放在缺氧预处理诱导的保护中起关键作用。最近，线粒体通透性转换孔的亲环蛋白-D成分已被证明与F1F0-ATP合酶相互作用并对其进行调节。然而，F1F0-ATP合酶的确切作用以及亲环蛋白-D与F1F0-ATP合酶在线粒体通透性转换孔和缺氧预处理中的相互作用仍不确定。在此，我们发现1小时的缺氧预处理可延迟线粒体DNA T8993G突变（NARP）骨肉瘤143B细胞杂交体（一种F1F0-ATP合酶缺陷细胞模型）在用包括过氧化氢、离子霉素和花生四烯酸在内的各种凋亡诱导剂刺激后的凋亡，并提高细胞存活率。这种缺氧预处理通过抑制活性氧的形成和防止心磷脂的消耗，保护NARP细胞杂交体免受聚焦激光照射诱导的氧化应激。此外，缺氧预处理可增强NARP细胞杂交体和野生型143B细胞中线粒体通透性转换孔短暂开放的保护功能。环孢素A破坏亲环蛋白-D与F1F0-ATP合酶之间的相互作用，减弱了缺氧预处理在NARP细胞杂交体和野生型143B细胞中诱导的线粒体保护作用。我们的结果表明，亲环蛋白-D与F1F0-ATP合酶之间的相互作用在缺氧预处理诱导的细胞保护中很重要。这一发现增进了我们对细胞响应缺氧预处理时线粒体通透性转换孔开放机制的理解，并将有助于进一步开发针对缺氧复氧损伤和线粒体介导的细胞死亡的新型药物。
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