<br>琥珀酸脱氢酶支持线粒体的代谢再利用以驱动炎症巨噬细胞。,Cell

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琥珀酸脱氢酶支持线粒体的代谢再利用以驱动炎症巨噬细胞。
Cell ( IF 45.5 ) Pub Date : 2016-Oct-06 , DOI: 10.1016/j.cell.2016.08.064
Evanna L Mills ₁ , Beth Kelly ₁ , Angela Logan ₂ , Ana S H Costa ₃ , Mukund Varma ₄ , Clare E Bryant ₅ , Panagiotis Tourlomousis ₅ , J Henry M Däbritz ₆ , Eyal Gottlieb ₆ , Isabel Latorre ₄ , Sinéad C Corr ₇ , Gavin McManus ₁ , Dylan Ryan ₁ , Howard T Jacobs ₈ , Marten Szibor ₉ , Ramnik J Xavier ₁₀ , Thomas Braun ₁₁ , Christian Frezza ₃ , Michael P Murphy ₂ , Luke A O'Neill ₁

Affiliation

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB23 8AQ, UK.
Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Department of Microbiology, Moyne Institute for Preventative Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland.
Institute of Biotechnology, 00014 University of Helsinki, P.O. Box 56, Helsinki 00014, Finland; BioMediTech and Tampere University Hospital, University of Tampere, Tampere 33014, Finland.
Institute of Biotechnology, 00014 University of Helsinki, P.O. Box 56, Helsinki 00014, Finland; BioMediTech and Tampere University Hospital, University of Tampere, Tampere 33014, Finland; Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.

活化的巨噬细胞经历代谢重编程，从而驱动其促炎表型，但其机制基础仍然不清楚。在这里，我们证明，在脂多糖 (LPS) 刺激下，巨噬细胞从通过氧化磷酸化产生 ATP 转变为糖酵解，同时还增加了琥珀酸水平。我们发现，通过琥珀酸脱氢酶（SDH）增加线粒体对琥珀酸的氧化，并提高线粒体膜电位，共同驱动线粒体活性氧（ROS）的产生。 RNA 测序表明，这种组合可诱导促炎基因表达谱，而琥珀酸氧化抑制剂丙二酸二甲酯 (DMM) 则可促进抗炎结果。通过解偶联线粒体或表达替代氧化酶 (AOX)，用鱼藤酮阻断 ROS 产生，抑制这种炎症表型，AOX 可以保护小鼠免受 LPS 致死。因此，巨噬细胞激活后发生的代谢改变将线粒体从 ATP 合成转变为 ROS 产生，以促进促炎状态。

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更新日期：2016-09-23

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