Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study
Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study
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DOI：
10.1111/bph.12179
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发表时间：
2013-07-01
影响因子：
7.3
通讯作者：
Boopathy, Rathanam
中科院分区：
文献类型：
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作者：
Chitra, Loganathan;Boopathy, Rathanam
背景与目的高原肺水肿（HAPE）是由线粒体氧化还原损伤引起的。因此，在大鼠肺中测定了低压缺氧（HH）诱导的线粒体生物合成和动力学基因表达的改变。此外，这种改变与线粒体DNA（mtDNA）编码的氧化磷酸化（mtOXPHOS）基因的表达相关。以地塞米松（DEX）对抗高原暴露所致线粒体损伤的预防作用为对照，了解高原暴露的适应性。将用DEX预处理的大鼠暴露于常压常氧（NN）或HH。HH诱导的损伤被评估为肺含水量、组织损伤和氧化剂生成的增加。测定线粒体数量、线粒体DNA含量和线粒体OXPHOS活性，以确定线粒体功能。研究了线粒体生物发生、动力学和mtOXPHOS基因的表达。关键结果HH诱导的肺损伤与线粒体数量、mtDNA含量和mtOXPHOS活性降低相关。HH暴露降低了核基因雌激素相关受体（ERR），该受体与控制线粒体代谢的过氧化物酶体增殖物激活因子（PGC-1）相互作用。因此，mtOXPHOS转录物在HH下被抑制。此外，HH通过减少线粒体融合蛋白2（Mfn 2）和增加裂变1（Fis 1）和动力蛋白相关蛋白1（Drp 1）表达来调节线粒体动力学。然而，在NN（即适应HH）下的DEX处理不影响线粒体生物发生和动力学，但增加mtOXPHOS转录。此外，mtOXPHOS活动增加与减少氧化剂的产生。此外，DEX预处理使ERR沿着线粒体动力学基因正常化，并增加mtOXPHOS转录物以引起HH下的线粒体功能。结论和意义HH压力（HAPE）介导的线粒体功能障碍是由于抑制ERR和mtOXPHOS转录。因此，ERR介导的线粒体生物能量学保护可能是肺适应HH所需的可能候选者。
Background and Purpose High-altitude pulmonary oedema (HAPE) experienced under high-altitude conditions is attributed to mitochondrial redox distress. Hence, hypobaric hypoxia (HH)-induced alteration in expression of mitochondrial biogenesis and dynamics genes was determined in rat lung. Further, such alteration was correlated with expression of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (mtOXPHOS) genes. The prophylactic effect of dexamethasone (DEX) in counteracting the HH-induced mitochondrial distress was used as control to understand adaptation to high-altitude exposure. Experimental Approach Rats pretreated with DEX were exposed to normobaric normoxia (NN) or HH. HH-induced injury was assessed as an increase in lung water content, tissue damage and oxidant generation. Mitochondrial number, mtDNA content and mtOXPHOS activities were measured to determine mitochondrial function. The expression of mitochondrial biogenesis, dynamics and mtOXPHOS genes was studied. Key Results HH-induced lung injury was associated with decreased mitochondrial number, mtDNA content and mtOXPHOS activities. HH exposure decreased the nuclear gene oestrogen-related receptor- (ERR), which interacts with PPAR- coactivator-1 (PGC-1) in controlling mitochondrial metabolism. Consequently, mtOXPHOS transcripts are repressed under HH. Further, HH modulated mitochondrial dynamics by decreasing mitofusin 2 (Mfn2) and augmenting fission 1 (Fis1) and dynamin-related protein 1 (Drp1) expression. Nevertheless, DEX treatment under NN (i.e. adaptation to HH) did not affect mitochondrial biogenesis and dynamics, but increased mtOXPHOS transcripts. Further, mtOXPHOS activities increased together with reduced oxidant generation. Also, DEX pretreatment normalized ERR along with mitochondrial dynamics genes and increased mtOXPHOS transcripts to elicit the mitochondrial function under HH. Conclusions and Implications HH stress (HAPE)-mediated mitochondrial dysfunction is due to repressed ERR and mtOXPHOS transcripts. Thus, ERR-mediated protection of mitochondrial bioenergetics might be the likely candidate required for lung adaptation to HH.