Hypoxic Regulation of Mitochondrial Metabolism and Mitophagy in Nucleus Pulposus Cells Is Dependent on HIF-1α-BNIP3 Axis.
Hypoxic Regulation of Mitochondrial Metabolism and Mitophagy in Nucleus Pulposus Cells Is Dependent on HIF-1α-BNIP3 Axis.
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髓核细胞中线粒体代谢与线粒体自噬的缺氧调节依赖于HIF-1α - BNIP3轴。
DOI：
10.1002/jbmr.4019
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发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
Risbud MV
中科院分区：
文献类型：
--
作者：
Madhu V;Boneski PK;Silagi E;Qiu Y;Kurland I;Guntur AR;Shapiro IM;Risbud MV
髓核（NP）细胞存在于椎间盘的无血管和缺氧的微环境中，并且由于强的HIF-1活性而主要是糖酵解的。通常认为，与依赖于氧化代谢的细胞相比，NP细胞含有很少的功能性线粒体。因此，线粒体对NP细胞代谢的贡献以及缺氧和HIF-1在线粒体稳态中的作用知之甚少。使用mitoQC报告小鼠，我们第一次表明，NP细胞线粒体在体内进行年龄依赖性线粒体自噬。从机制上讲，体外研究表明，在缺氧条件下，原代NP细胞中的线粒体经历HIF-1α依赖性片段化，其通过调节分别参与线粒体分裂和融合的关键蛋白DRP 1和OPA 1的水平来控制。Seahorse分析和稳态代谢分析结合[1-2- 13 C]-葡萄糖通量分析显示，在缺氧条件下，HIF-1α通过协调糖酵解和线粒体TCA循环相互作用调节代谢通量，从而控制NP细胞的总体生物合成能力。我们进一步表明，缺氧和HIF-1α通过BNIP 3（一种受体介导的线粒体自噬的诱导剂）的线粒体转位触发NP细胞的线粒体自噬。然而，令人惊讶的是，体外HIF-1α的缺失和对NP特异性HIF-1α缺失小鼠的分析并未显示NP细胞中线粒体吞噬通量的减少，而是线粒体数量较高的NIX和PINK 1-Parkin途径的代偿性增加。总之，我们的研究为缺氧和HIF-1α信号转导对NP细胞线粒体代谢和质量控制之间的复杂相互作用提供了新的机制见解。
Nucleus pulposus (NP) cells reside in an avascular and hypoxic microenvironment of intervertebral discs and are predominantly glycolytic due to robust HIF-1 activity. It is generally thought that NP cells contain few functional mitochondria compared to cells that rely on oxidative metabolism. Consequently, the contribution of mitochondria to NP cell metabolism and the role of hypoxia and HIF-1 in mitochondrial homeostasis is poorly understood. Using mitoQC reporter mice, we show for the first time that NP cell mitochondria undergo age-dependent mitophagy in vivo. Mechanistically, in vitro studies suggest that, under hypoxic conditions, mitochondria in primary NP cells undergo HIF-1α dependent fragmentation, controlled by modulating the levels of key proteins DRP1 and OPA1 that are involved in mitochondrial fission and fusion respectively. Seahorse assays and steady state metabolic profiling coupled with [1–2-13C]-glucose flux analysis revealed that in hypoxia, HIF-1α regulated metabolic flux through coordinating glycolysis and the mitochondrial TCA cycle interactions, thereby controlling the overall biosynthetic capacity of NP cells. We further show that hypoxia and HIF-1α trigger mitophagy in NP cells through the mitochondrial translocation of BNIP3, an inducer of receptor-mediated mitophagy. Surprisingly, however, loss of HIF-1α in vitro and analysis of NP-specific HIF-1α null mice do not show a decrease in mitophagic flux in NP cells but a compensatory increase in NIX and PINK1-Parkin pathways with higher mitochondrial number. Taken together, our studies provide novel mechanistic insights into the complex interplay between hypoxia and HIF-1α signaling on the mitochondrial metabolism and quality control in NP cells.
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