Mitochondrial phosphatidylethanolamine synthesis affects mitochondrial energy metabolism and quiescence entry through attenuation of Snf1/AMPK signaling in yeast
Mitochondrial phosphatidylethanolamine synthesis affects mitochondrial energy metabolism and quiescence entry through attenuation of Snf1/AMPK signaling in yeast
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DOI：
10.1096/fj.202101600rr
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发表时间：
2022-07-01
期刊：
影响因子：
4.8
通讯作者：
Kuge，Osamu
中科院分区：
文献类型：
--
作者：
Miyata，Non;Ito，Takanori;Kuge，Osamu
Ups2‐Mdm35复合物介导线粒体内磷脂酰丝氨酸（PS）转运，促进线粒体磷脂酰乙醇胺（PE）合成。在本研究中，我们发现ups2∆酵母显示出线粒体ATP产量增加，并且在双氧转换后阶段增加了静止（G0）进入。转录组学和生化分析显示，Ups2的缺失导致酵母AMPK同源基因Snf1的过度激活。通过消耗Snf1激活激酶，Sak1使Snf1失活，取消了线粒体ATP产生的变化，并在ups2∆细胞中观察到休眠进入。此外，在Snf1调控的因子中，丙酮酸羧化酶Pyc1上调和乙酰辅酶a羧化酶Acc1下调足以增加线粒体ATP的产生和进入静止状态。这些结果表明，Ups2‐Mdm35复合物介导的正常PE合成会减弱Snf1/AMPK活性，并且Snf1介导的碳代谢调节对线粒体能量代谢和休眠进入有很大影响。我们还发现，Ups2和细胞周期调控因子wh5和wh7 （Rb1肿瘤抑制因子的功能同源物）的缺失会导致酵母的合成生长缺陷。同样，敲低Ups2的人类同源物PRELID3b，可以降低Rb1‐缺陷乳腺癌细胞的活力，这表明PRELID3b是癌症治疗的潜在靶点。
The Ups2‐Mdm35 complex mediates intramitochondrial phosphatidylserine (PS) transport to facilitate mitochondrial phosphatidylethanolamine (PE) synthesis. In the present study, we found thatups2∆yeast showed increased mitochondrial ATP production and enhanced quiescence (G0) entry in the post‐diauxic shift phase. Transcriptomic and biochemical analyses revealed that the depletion of Ups2 leads to overactivation of the yeast AMPK homolog Snf1. Inactivation of Snf1 by depletion of an Snf1‐activating kinase, Sak1 canceled the changes in mitochondrial ATP production and quiescence entry observed inups2∆cells. Furthermore, among the factors regulated by Snf1, upregulation of pyruvate carboxylase, Pyc1 and downregulation of acetyl‐CoA carboxylase, Acc1, respectively, were sufficient to increase mitochondrial ATP production and quiescence entry. These results suggested that a normal PE synthesis mediated by Ups2‐Mdm35 complex attenuates Snf1/AMPK activity, and that Snf1‐mediated regulation of carbon metabolisms has great impacts on mitochondrial energy metabolism and quiescence entry. We also found that depletion of Ups2 together with the cell‐cycle regulators Whi5 and Whi7, functional orthologs of the Rb1 tumor suppressor, caused a synthetic growth defect in yeast. Similarly, knockdown of PRELID3b, the human homolog of Ups2, decreased the viability of Rb1‐deficient breast cancer cells, suggesting that PRELID3b is a potential target for cancer therapy.