Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift.
Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift.
复制标题
DOI：
10.1074/jbc.ra118.003200
复制
发表时间：
2018-05-25
期刊：
影响因子：
--
通讯作者：
Criddle DN
中科院分区：
文献类型：
--
作者：
Armstrong JA;Cash NJ;Ouyang Y;Morton JC;Chvanov M;Latawiec D;Awais M;Tepikin AV;Sutton R;Criddle DN
线粒体功能障碍是急性胰腺炎（AP）的核心。不同的AP刺激诱导线粒体通透性转换孔（MPTP）的Ca 2+依赖性形成，MPTP是由亲环素D（CypD）调节的溶质通道，其形成导致ATP耗尽和坏死。据报道，氧化应激触发MPTP形成，并在临床AP中升高，但活性氧如何影响细胞死亡尚不清楚。在这里，我们评估了潜在的MPTP参与氧化剂诱导的胰腺腺泡细胞生物能量学和命运的影响。低浓度（1-10 μm）的H2 O2促进腺泡细胞凋亡，高浓度（0.5-1 μ m）的H2 O2引起腺泡细胞迅速坏死。H2 O2还以浓度依赖性方式降低线粒体NADH/FAD+氧化还原比和Δ Δ Km（10 μm ~ 1 mm H2 O2），在500 μm H2 O2时作用最大。H_2O_2降低腺泡细胞的基础耗氧率，但在<50 μ mH_2O_2时，对ATP转换无影响。然而，较高的H2 O2水平（≥50 μm）会减少备用呼吸能力和ATP周转，生物能崩溃，ATP耗竭和细胞死亡。甲萘醌产生有害的生物能量效应类似于H2 O2，这是由抗氧化剂N-乙酰半胱氨酸抑制。氧化剂诱导的生物能量变化、ΔΨm的损失和细胞死亡并没有通过CypD的基因缺失或环孢菌素A的急性抑制而得到改善。这些结果表明，氧化应激改变线粒体生物能量学和修改胰腺腺泡细胞死亡。从细胞凋亡到坏死的转变似乎与线粒体备用呼吸能力和ATP产生的减少有关，这些影响独立于CypD敏感的MPTP形成。
Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+-dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), the formation of which causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate. H2O2 application promoted acinar cell apoptosis at low concentrations (1–10 μm), whereas higher levels (0.5–1 mm) elicited rapid necrosis. H2O2 also decreased the mitochondrial NADH/FAD+ redox ratio and ΔΨm in a concentration-dependent manner (10 μm to 1 mm H2O2), with maximal effects at 500 μm H2O2. H2O2 decreased the basal O2 consumption rate of acinar cells, with no alteration of ATP turnover at <50 μm H2O2. However, higher H2O2 levels (≥50 μm) diminished spare respiratory capacity and ATP turnover, and bioenergetic collapse, ATP depletion, and cell death ensued. Menadione exerted detrimental bioenergetic effects similar to those of H2O2, which were inhibited by the antioxidant N-acetylcysteine. Oxidant-induced bioenergetic changes, loss of ΔΨm, and cell death were not ameliorated by genetic deletion of CypD or by its acute inhibition with cyclosporine A. These results indicate that oxidative stress alters mitochondrial bioenergetics and modifies pancreatic acinar cell death. A shift from apoptosis to necrosis appears to be associated with decreased mitochondrial spare respiratory capacity and ATP production, effects that are independent of CypD-sensitive MPTP formation.