Martínez-Reyes Inmaculada, Diebold Lauren P, Kong Hyewon, Schieber Michael, Huang He, Hensley Christopher T, Mehta Manan M, Wang Tianyuan, Santos Janine H, Woychik Richard, Dufour Eric, Spelbrink Johannes N, Weinberg Samuel E, Zhao Yingming, DeBerardinis Ralph J, Chandel Navdeep S
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Mol Cell. 2016 Jan 21;61(2):199-209. doi: 10.1016/j.molcel.2015.12.002. Epub 2015 Dec 24.
Mitochondrial metabolism is necessary for the maintenance of oxidative TCA cycle function and mitochondrial membrane potential. Previous attempts to decipher whether mitochondria are necessary for biological outcomes have been hampered by genetic and pharmacologic methods that simultaneously disrupt multiple functions linked to mitochondrial metabolism. Here, we report that inducible depletion of mitochondrial DNA (ρ(ο) cells) diminished respiration, oxidative TCA cycle function, and the mitochondrial membrane potential, resulting in diminished cell proliferation, hypoxic activation of HIF-1, and specific histone acetylation marks. Genetic reconstitution only of the oxidative TCA cycle function specifically in these inducible ρ(ο) cells restored metabolites, resulting in re-establishment of histone acetylation. In contrast, genetic reconstitution of the mitochondrial membrane potential restored ROS, which were necessary for hypoxic activation of HIF-1 and cell proliferation. These results indicate that distinct mitochondrial functions associated with respiration are necessary for cell proliferation, epigenetics, and HIF-1 activation.
线粒体代谢对于维持氧化三羧酸循环功能和线粒体膜电位是必需的。此前，通过遗传和药理学方法来破译线粒体对于生物学结果是否必要的尝试受到了阻碍，因为这些方法会同时破坏与线粒体代谢相关的多种功能。在此，我们报告称，线粒体DNA的诱导性耗竭（ρ(ο)细胞）会降低呼吸作用、氧化三羧酸循环功能以及线粒体膜电位，导致细胞增殖减少、缺氧诱导因子-1（HIF-1）的低氧激活以及特定的组蛋白乙酰化标记减少。仅在这些诱导性ρ(ο)细胞中特异性地对氧化三羧酸循环功能进行基因重建可恢复代谢产物，从而重新建立组蛋白乙酰化。相比之下，线粒体膜电位的基因重建可恢复活性氧（ROS），而ROS对于HIF-1的低氧激活和细胞增殖是必需的。这些结果表明，与呼吸作用相关的不同线粒体功能对于细胞增殖、表观遗传学和HIF-1激活是必需的。
