Sizek Herbert, Deritei Dávid, Fleig Katherine, Harris Marlayna, Regan Peter L, Glass Kimberly, Regan Erzsébet Ravasz
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital / Harvard Medical School, Boston, MA 02115, USA.
Transl Oncol. 2024 Nov;49:102084. doi: 10.1016/j.tranon.2024.102084. Epub 2024 Aug 19.
The steady accumulation of senescent cells with aging creates tissue environments that aid cancer evolution. Aging cell states are highly heterogeneous. 'Deep senescent' cells rely on healthy mitochondria to fuel a strong proinflammatory secretome, including cytokines, growth and transforming signals. Yet, the physiological triggers of senescence such as reactive oxygen species (ROS) can also trigger mitochondrial dysfunction, and sufficient energy deficit to alter their secretome and cause chronic oxidative stress - a state termed Mitochondrial Dysfunction-Associated Senescence (MiDAS). Here, we offer a mechanistic hypothesis for the molecular processes leading to MiDAS, along with testable predictions. To do this we have built a Boolean regulatory network model that qualitatively captures key aspects of mitochondrial dynamics during cell cycle progression (hyper-fusion at the G1/S boundary, fission in mitosis), apoptosis (fission and dysfunction) and glucose starvation (reversible hyper-fusion), as well as MiDAS in response to SIRT3 knockdown or oxidative stress. Our model reaffirms the protective role of NAD and external pyruvate. We offer testable predictions about the growth factor- and glucose-dependence of MiDAS and its reversibility at different stages of reactive oxygen species (ROS)-induced senescence. Our model provides mechanistic insights into the distinct stages of DNA-damage induced senescence, the relationship between senescence and epithelial-to-mesenchymal transition in cancer and offers a foundation for building multiscale models of tissue aging.
衰老细胞随年龄增长而不断积累，从而形成有助于癌症演变的组织环境。衰老细胞状态具有高度异质性。“深度衰老”细胞依赖健康的线粒体来为强大的促炎分泌组提供能量，该分泌组包括细胞因子、生长和转化信号。然而，衰老的生理触发因素，如活性氧（ROS），也会引发线粒体功能障碍，以及足够的能量不足，从而改变其分泌组并导致慢性氧化应激——一种称为线粒体功能障碍相关衰老（MiDAS）的状态。在这里，我们提出了一个关于导致MiDAS的分子过程的机制假说，以及可测试的预测。为此，我们构建了一个布尔调控网络模型，该模型定性地捕捉了细胞周期进程中线粒体动力学的关键方面（G1/S边界处的超融合、有丝分裂中的裂变）、细胞凋亡（裂变和功能障碍）和葡萄糖饥饿（可逆性超融合），以及对SIRT3敲低或氧化应激的MiDAS。我们的模型再次证实了NAD和外部丙酮酸的保护作用。我们提供了关于MiDAS对生长因子和葡萄糖的依赖性及其在活性氧（ROS）诱导的衰老不同阶段的可逆性方面的可测试预测。我们的模型为DNA损伤诱导的衰老的不同阶段、衰老与癌症中上皮-间质转化之间的关系提供了机制性见解，并为构建组织衰老的多尺度模型奠定了基础。
