• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

功能失调的氧化磷酸化癌细胞需要内质网到线粒体的 Ca 转移来维持生存。

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca transfer for survival.

机构信息

Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile.

Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile.

出版信息

Sci Signal. 2020 Jul 14;13(640):eaay1212. doi: 10.1126/scisignal.aay1212.

DOI:10.1126/scisignal.aay1212
PMID:32665411
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9387586/
Abstract

Spontaneous Ca signaling from the InsPR intracellular Ca release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca uptake in regulating bioenergetics in these cells, we used OXPHOS-competent and OXPHOS-defective cells. Inhibition of InsPR activity or mitochondrial Ca uptake increased α-ketoglutarate (αKG) abundance and the NAD/NADH ratio, indicating that constitutive endoplasmic reticulum (ER)-to-mitochondria Ca transfer promoted optimal αKG dehydrogenase (αKGDH) activity. Reducing mitochondrial Ca inhibited αKGDH activity and increased NAD, which induced SIRT1-dependent autophagy in both OXPHOS-competent and OXPHOS-defective cells. Whereas autophagic flux in OXPHOS-competent cells promoted cell survival, it was impaired in OXPHOS-defective cells because of inhibition of autophagosome-lysosome fusion. Inhibition of αKGDH and impaired autophagic flux in OXPHOS-defective cells resulted in pronounced cell death in response to interruption of constitutive flux of Ca from ER to mitochondria. These results demonstrate that mitochondria play a fundamental role in maintaining bioenergetic homeostasis of both OXPHOS-competent and OXPHOS-defective cells, with Ca regulation of αKGDH activity playing a pivotal role. Inhibition of ER-to-mitochondria Ca transfer may represent a general therapeutic strategy against cancer cells regardless of their OXPHOS status.

摘要

内质网钙释放通道到线粒体的自发钙信号对于最佳氧化磷酸化 (OXPHOS) 和 ATP 产生是必需的。在 OXPHOS 有缺陷的细胞中，还原性羧化作用取代氧化代谢来维持还原当量和代谢前体的含量。为了研究线粒体钙摄取在调节这些细胞生物能量学中的作用，我们使用了 OXPHOS 功能正常和 OXPHOS 有缺陷的细胞。InsPR 活性或线粒体钙摄取的抑制增加了α-酮戊二酸 (αKG) 的丰度和 NAD/NADH 比，表明组成型内质网 (ER) 到线粒体钙转移促进了最佳的αKG 脱氢酶 (αKGDH) 活性。减少线粒体钙抑制了αKGDH 活性并增加了 NAD，这在 OXPHOS 功能正常和 OXPHOS 有缺陷的细胞中诱导了 SIRT1 依赖性自噬。尽管 OXPHOS 功能正常的细胞中的自噬通量促进了细胞存活，但在 OXPHOS 有缺陷的细胞中，由于自噬体溶酶体融合的抑制而受损。在 OXPHOS 有缺陷的细胞中，αKGDH 的抑制和自噬通量的受损导致钙从 ER 到线粒体的组成型通量中断时明显的细胞死亡。这些结果表明，线粒体在维持 OXPHOS 功能正常和 OXPHOS 有缺陷的细胞的生物能量学稳态中起着基本作用，钙调节αKGDH 活性起着关键作用。抑制 ER 到线粒体的钙转移可能代表一种针对癌症细胞的通用治疗策略，而与它们的 OXPHOS 状态无关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/2428ce700198/nihms-1829156-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/c8d0956ca3ee/nihms-1829156-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/82b89e34b534/nihms-1829156-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/0c7bb9f45352/nihms-1829156-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/a5e960176a4c/nihms-1829156-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/2428ce700198/nihms-1829156-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/c8d0956ca3ee/nihms-1829156-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/82b89e34b534/nihms-1829156-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/0c7bb9f45352/nihms-1829156-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/a5e960176a4c/nihms-1829156-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46fc/9387586/2428ce700198/nihms-1829156-f0005.jpg

相似文献

1
Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca transfer for survival.功能失调的氧化磷酸化癌细胞需要内质网到线粒体的 Ca 转移来维持生存。
Sci Signal. 2020 Jul 14;13(640):eaay1212. doi: 10.1126/scisignal.aay1212.
2
Mitochondrial VDAC, the Na/Ca Exchanger, and the Ca Uniporter in Ca Dynamics and Signaling.线粒体电压依赖性阴离子通道、钠/钙交换器和钙单向通道在钙动力学和信号转导中的作用。
Adv Exp Med Biol. 2017;981:323-347. doi: 10.1007/978-3-319-55858-5_13.
3
Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism.内质网（ER）氧化还原控制与线粒体代谢之间的机制联系。
Cells. 2019 Sep 12;8(9):1071. doi: 10.3390/cells8091071.
4
α-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions.α-突触核蛋白通过增强内质网-线粒体相互作用来控制线粒体钙离子稳态。
J Biol Chem. 2012 May 25;287(22):17914-29. doi: 10.1074/jbc.M111.302794. Epub 2012 Mar 27.
5
Endoplasmic Reticulum-Mitochondria Communication Through Ca Signaling: The Importance of Mitochondria-Associated Membranes (MAMs).通过钙信号实现的内质网-线粒体通讯：线粒体相关膜（MAMs）的重要性。
Adv Exp Med Biol. 2017;997:49-67. doi: 10.1007/978-981-10-4567-7_4.
6
Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites.自噬通过线粒体-内质网接触位点调节脂肪酸氧化磷酸化的可用性。
Nat Commun. 2020 Aug 13;11(1):4056. doi: 10.1038/s41467-020-17882-2.
7
NLRX1 regulates TNF-α-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells.NLRX1 调控 TNF-α 诱导的线粒体-溶酶体串扰以维持乳腺癌细胞的侵袭和转移能力。
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1460-1476. doi: 10.1016/j.bbadis.2019.02.018. Epub 2019 Feb 23.
8
MTOR-independent autophagy induced by interrupted endoplasmic reticulum-mitochondrial Ca communication: a dead end in cancer cells.被中断的内质网-线粒体钙通讯诱导的 MTOR 非依赖性自噬：癌细胞的死胡同。
Autophagy. 2019 Feb;15(2):358-361. doi: 10.1080/15548627.2018.1537769. Epub 2018 Oct 29.
9
Molecularly distinct routes of mitochondrial Ca2+ uptake are activated depending on the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA).根据肌浆网/内质网 Ca2+-ATP 酶（SERCA）的活性，可激活分子上不同的线粒体 Ca2+摄取途径。
J Biol Chem. 2013 May 24;288(21):15367-79. doi: 10.1074/jbc.M113.462259. Epub 2013 Apr 16.
10
Distinct intracellular sAC-cAMP domains regulate ER Ca signaling and OXPHOS function.不同细胞内的 sAC-cAMP 结构域调节内质网 Ca 信号和 OXPHOS 功能。
J Cell Sci. 2017 Nov 1;130(21):3713-3727. doi: 10.1242/jcs.206318. Epub 2017 Sep 1.

引用本文的文献

1
Deciphering Mitochondria: Unveiling Their Roles in Mechanosensing and Mechanotransduction.解读线粒体：揭示其在机械传感和机械转导中的作用。
Research (Wash D C). 2025 Aug 8;8:0816. doi: 10.34133/research.0816. eCollection 2025.
2
Deciphering the Regulatory Potential of Antioxidant and Electron-Shuttling Bioactive Compounds in Oolong Tea.解读乌龙茶中抗氧化和电子穿梭生物活性化合物的调节潜力。
Biology (Basel). 2025 Apr 28;14(5):487. doi: 10.3390/biology14050487.
3
Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.

本文引用的文献

1
Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer.肿瘤相关成纤维细胞通过代谢重排和线粒体转移促进前列腺癌恶性进展。
Oncogene. 2019 Jul;38(27):5339-5355. doi: 10.1038/s41388-019-0805-7. Epub 2019 Apr 1.
2
Resveratrol inhibits cancer cell proliferation by impairing oxidative phosphorylation and inducing oxidative stress.白藜芦醇通过损害氧化磷酸化和诱导氧化应激来抑制癌细胞增殖。
Toxicol Appl Pharmacol. 2019 May 1;370:65-77. doi: 10.1016/j.taap.2019.03.008. Epub 2019 Mar 13.
3
Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways.
线粒体-细胞器间串扰在建立区室化代谢稳态中的作用
Mol Cell. 2025 Apr 17;85(8):1487-1508. doi: 10.1016/j.molcel.2025.03.003.
4
Nanotechnology-Fortified Manipulation of Cell Ca Signaling.纳米技术强化的细胞钙信号调控
Small Sci. 2024 Jun 26;4(10):2400169. doi: 10.1002/smsc.202400169. eCollection 2024 Oct.
5
CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.细胞周期蛋白依赖性激酶4失活通过三阴性乳腺癌中线粒体-内质网接触重塑抑制细胞凋亡。
Nat Commun. 2025 Jan 9;16(1):541. doi: 10.1038/s41467-024-55605-z.
6
The IPR inhibitor desmethylxestospongin B reduces tumor cell migration, invasion and metastasis by impairing lysosome acidification and β1-integrin recycling.IPR 抑制剂去甲氧基西沙必利 B 通过破坏溶酶体酸化和β1 整合素再循环来减少肿瘤细胞迁移、侵袭和转移。
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167557. doi: 10.1016/j.bbadis.2024.167557. Epub 2024 Oct 31.
7
Mitochondrial division inhibitor (mdivi-1) induces extracellular matrix (ECM)-detachment of viable breast cancer cells by a DRP1-independent mechanism.线粒体分裂抑制剂（mdivi-1）通过一种不依赖于 DRP1 的机制诱导活的乳腺癌细胞脱离细胞外基质（ECM）。
Sci Rep. 2024 Jun 19;14(1):14178. doi: 10.1038/s41598-024-64228-9.
8
Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.内质网-线粒体通讯异常是线粒体疾病的常见病理机制。
Cell Death Dis. 2024 Jun 10;15(6):405. doi: 10.1038/s41419-024-06781-9.
9
Scalable Total Synthesis of (+)-Desmethylxestospongin B.可扩展的 (+)-去甲异海松烷酮 B 的全合成。
J Org Chem. 2024 Jun 7;89(11):8120-8130. doi: 10.1021/acs.joc.4c00779. Epub 2024 May 29.
10
Novel Inositol 1,4,5-Trisphosphate Receptor Inhibitor Antagonizes Hepatic Stellate Cell Activation: A Potential Drug to Treat Liver Fibrosis.新型肌醇 1,4,5-三磷酸受体抑制剂拮抗肝星状细胞活化：治疗肝纤维化的潜在药物。
Cells. 2024 Apr 30;13(9):765. doi: 10.3390/cells13090765.
藤黄酚通过内质网应激和线粒体应激依赖途径诱导胰腺癌细胞自噬。
Cell Death Dis. 2019 Feb 13;10(2):142. doi: 10.1038/s41419-019-1366-y.
4
Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency.线粒体靶向抗氧化剂 MitoQ 在 IDH2 缺乏诱导的线粒体 ROS 引起的感觉神经性听力损失中的治疗潜力。
Redox Biol. 2019 Jan;20:544-555. doi: 10.1016/j.redox.2018.11.013. Epub 2018 Nov 20.
5
Revisiting the Warburg Effect: Some Tumors Hold Their Breath.重新审视瓦堡效应：有些肿瘤会屏气。
Cell Metab. 2018 Nov 6;28(5):669-670. doi: 10.1016/j.cmet.2018.10.011.
6
MTOR-independent autophagy induced by interrupted endoplasmic reticulum-mitochondrial Ca communication: a dead end in cancer cells.被中断的内质网-线粒体钙通讯诱导的 MTOR 非依赖性自噬：癌细胞的死胡同。
Autophagy. 2019 Feb;15(2):358-361. doi: 10.1080/15548627.2018.1537769. Epub 2018 Oct 29.
7
FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway.FR58P1a；一种新型的 OXPHOS 解偶联剂，通过 Sirt1/AMPK/β1-整合素途径抑制三阴性乳腺癌细胞的迁移。
Sci Rep. 2018 Sep 4;8(1):13190. doi: 10.1038/s41598-018-31367-9.
8
α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis.α-酮戊二酸脱氢酶抑制可拮抗乳腺癌相关的肺转移。
Cell Death Dis. 2018 Jul 9;9(7):756. doi: 10.1038/s41419-018-0802-8.
9
Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.氯喹通过减少自噬体-溶酶体融合来抑制自噬流。
Autophagy. 2018;14(8):1435-1455. doi: 10.1080/15548627.2018.1474314. Epub 2018 Jul 20.
10
An inhibitor of oxidative phosphorylation exploits cancer vulnerability.一种抑制氧化磷酸化的物质利用了癌症的脆弱性。
Nat Med. 2018 Jul;24(7):1036-1046. doi: 10.1038/s41591-018-0052-4. Epub 2018 Jun 11.