Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia
Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia
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DOI：
10.1128/mcb.01402-14
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发表时间：
2015-05-01
影响因子：
5.3
通讯作者：
Mazure, Nathalie M.
中科院分区：
文献类型：
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作者：
Brahimi-Horn, M. Christiane;Lacas-Gervais, Sandra;Mazure, Nathalie M.
肿瘤的氧限制（缺氧）微环境诱导代谢重编程和细胞存活，但涉及线粒体的潜在机制仍然知之甚少。我们以前证明，缺氧诱导因子1介导的过度融合的线粒体诱导Bcl-2/腺病毒E1 B 19 kDa相互作用蛋白3和翻译后截断的线粒体ATP转运外膜电压依赖性阴离子通道1在缺氧细胞。此外，我们发现截短与药物诱导的细胞凋亡的抗性增加有关，并表明患者的化疗抗性增加。我们现在表明，沉默的肿瘤抑制因子TP 53减少截短和增加药物诱导的细胞凋亡。我们还表明，TP 53调节截断通过诱导线粒体蛋白Mieap。虽然我们发现截短与线粒体自噬无关，但我们在培养的缺氧细胞和患者肿瘤组织中观察到线粒体和内溶酶体之间的局部微融合。由于我们发现，内溶酶体天冬酰胺内肽酶是负责截断，我们建议，这是一个读出器的细胞内溶酶体微融合缺氧。这些新的发现提供了一个框架，更好地了解缺氧细胞代谢和细胞存活，通过低氧诱导因子1和TP 53调节的神经元-内溶酶体微融合。
The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and post-translational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53.