König Jeannette, Ott Christiane, Hugo Martín, Jung Tobias, Bulteau Anne-Laure, Grune Tilman, Höhn Annika
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), 10117 Berlin, Germany.
Redox Biol. 2017 Apr;11:673-681. doi: 10.1016/j.redox.2017.01.017. Epub 2017 Jan 25.
Mitochondria have been in the focus of oxidative stress and aging research for decades due to their permanent production of ROS during the oxidative phosphorylation. The hypothesis exists that mitochondria are involved in the formation of lipofuscin, an autofluorescent protein aggregate that accumulates progressively over time in lysosomes of post-mitotic and senescent cells. To investigate the influence and involvement of mitochondria in lipofuscinogenesis, we analyzed lipofuscin amounts as well as the mitochondrial function in young and senescent cells. In addition we used an aging model and Lon protease deficient HeLa cells to investigate the influence of mitochondrial degradation processes on lipofuscin formation. We were able to show that mitophagy is impaired in senescent cells resulting in an increased mitochondrial mass and superoxide formation. In addition, the inhibition of mitochondrial fission leads to increased lipofuscin formation. Moreover, we observed that Lon protease downregulation is linked to a higher lipofuscinogenesis whereas the application of the mitochondrial-targeted antioxidant mitoTEMPO is able to prevent the accumulation of this protein aggregate.
几十年来，线粒体一直是氧化应激和衰老研究的焦点，因为它们在氧化磷酸化过程中持续产生活性氧（ROS）。有一种假说认为，线粒体参与了脂褐素的形成，脂褐素是一种自发荧光蛋白聚集体，随着时间的推移在有丝分裂后细胞和衰老细胞的溶酶体中逐渐积累。为了研究线粒体在脂褐素生成中的影响和作用，我们分析了年轻细胞和衰老细胞中脂褐素的含量以及线粒体功能。此外，我们使用了衰老模型和Lon蛋白酶缺陷的HeLa细胞来研究线粒体降解过程对脂褐素形成的影响。我们能够证明，衰老细胞中的线粒体自噬受损，导致线粒体质量增加和超氧化物生成。此外，线粒体分裂的抑制会导致脂褐素形成增加。此外，我们观察到Lon蛋白酶下调与更高的脂褐素生成有关，而应用线粒体靶向抗氧化剂mitoTEMPO能够防止这种蛋白聚集体的积累。
