Institute of Biological Chemistry and Nutrition, Department of Biofunctionality and Food Safety, University of Hohenheim, 70593 Stuttgart, Germany.
Free Radic Biol Med. 2010 Apr 15;48(8):1100-8. doi: 10.1016/j.freeradbiomed.2010.01.030. Epub 2010 Jan 29.
Aging is accompanied by an intracellular accumulation of lipofuscin, a hydrophobic yellow-brownish material that accumulates especially in the lysosomal compartment, where it can be neither degraded nor exocytosed from the cell. The intracellular effects of accumulating lipofuscin are still a subject of speculation. In addition to the demonstrated inhibition of the proteasome, it was proposed that lipofuscin is cytotoxic because of its ability to incorporate transition metals such as copper and iron, resulting in a redox-active surface, able to catalyze the Fenton reaction. This characteristic of lipofuscin may contribute to an increased level of radical formation and oxidatively modified cellular components such as proteins, lipids, and RNA/DNA, which has been shown to be extensive in aging cells. In this study for the first time the lipofuscin-mediated formation of oxidants and the role of iron in this process are directly shown in a model of senescent fibroblasts, as well as in vitro with artificial lipofuscin. We demonstrate that this oxidant production is independent of mitochondria and has cytotoxic effects. The ability of lipofuscin to produce oxidants is dependent on the amount of transition metals incorporated. Although the amount of oxidants formed by cellular lipofuscin turned out to be moderate, it is chronic and thus lipofuscin is able to catalyze its own formation.
衰老是伴随着脂褐素在内细胞堆积的，脂褐素是一种疏水性的黄棕色物质，尤其在溶酶体中积累，在溶酶体中既不能降解也不能从细胞中排出。积累的脂褐素对细胞内的影响仍在推测之中。除了已经证明的对蛋白酶体的抑制作用外，还有人提出脂褐素由于能够结合过渡金属如铜和铁，从而具有细胞毒性，产生具有氧化还原活性的表面，能够催化芬顿反应。脂褐素的这种特性可能导致自由基形成水平增加，并导致蛋白质、脂质和 RNA/DNA 等细胞成分发生氧化修饰，这在衰老细胞中已经得到了广泛的证实。在这项研究中，首次直接在衰老成纤维细胞模型以及体外人工脂褐素中显示了脂褐素介导的氧化剂形成和铁在这一过程中的作用。我们证明这种氧化剂的产生与线粒体无关，并且具有细胞毒性。脂褐素产生氧化剂的能力取决于结合的过渡金属的数量。尽管细胞脂褐素形成的氧化剂数量适中，但它是慢性的，因此脂褐素能够催化其自身的形成。
