Grimm Carolin, Osiewacz Heinz D
Johann Wolfgang Goethe University, Faculty for Biosciences & Cluster of Excellence 'Macromolecular Complexes' Frankfurt, Institute of Molecular Biosciences, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Johann Wolfgang Goethe University, Faculty for Biosciences & Cluster of Excellence 'Macromolecular Complexes' Frankfurt, Institute of Molecular Biosciences, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Exp Gerontol. 2015 Mar;63:8-17. doi: 10.1016/j.exger.2015.01.042. Epub 2015 Jan 20.
For biological systems, balancing cellular levels of reactive oxygen species (ROS) is of great importance because ROS are both, essential for cellular signaling and dangerous in causing molecular damage. Cellular ROS abundance is controlled by a delicate network of molecular pathways. Within this network, superoxide dismutases (SODs) are active in disproportion of the superoxide anion leading to the formation of hydrogen peroxide. The fungal aging model Podospora anserina encodes at least three SODs. One of these is the mitochondrial PaSOD3 isoform containing manganese as a cofactor. Previous work resulted in the selection of strains in which PaSod3 is strongly overexpressed. These strains display impairments in growth and lifespan. A computational model suggests a series of events to occur in Sod3 overexpressing strains leading to adverse effects due to elevated hydrogen peroxide levels. In an attempt to validate this model and to obtain more detailed information about the cellular responses involved in ROS balancing, we further investigated the PaSod3 overexpressing strains. Here we show that hydrogen peroxide levels are indeed strongly increased in the mutant strain. Surprisingly, this phenotype can be rescued by the addition of manganese to the growth medium. Strikingly, while we obtained no evidence for an antioxidant effect of manganese, we found that the metal is required for induction of components of the ROS scavenging network and lowers the hydrogen peroxide level of the mutant. A similar effect of manganese on lifespan reversion was obtained in wild-type strains challenged with exogenous hydrogen peroxide. It appears that manganese is limited under high hydrogen peroxide and suggests that a manganese-dependent activity leads to the induction of ROS scavenging components.
对于生物系统而言，平衡细胞内活性氧（ROS）水平至关重要，因为ROS对于细胞信号传导必不可少，但同时也会造成分子损伤，十分危险。细胞内ROS的丰度由一个精密的分子通路网络控制。在这个网络中，超氧化物歧化酶（SOD）可将超氧阴离子歧化，生成过氧化氢。真菌衰老模型嗜热栖热放线菌至少编码三种SOD。其中之一是线粒体中的PaSOD3亚型，其辅因子为锰。此前的研究筛选出了PaSod3强烈过表达的菌株。这些菌株在生长和寿命方面存在缺陷。一个计算模型表明，在Sod3过表达的菌株中会发生一系列事件，由于过氧化氢水平升高而导致不良反应。为了验证该模型，并获得更多关于ROS平衡所涉及的细胞反应的详细信息，我们进一步研究了PaSod3过表达菌株。我们在此表明，突变菌株中的过氧化氢水平确实大幅升高。令人惊讶的是，向生长培养基中添加锰可以挽救这种表型。引人注目的是，虽然我们没有发现锰具有抗氧化作用的证据，但我们发现这种金属是诱导ROS清除网络成分所必需的，并且可以降低突变体中的过氧化氢水平。在用外源性过氧化氢处理的野生型菌株中，锰对寿命逆转也有类似的作用。似乎在高过氧化氢水平下锰是有限的，这表明锰依赖性活性会导致ROS清除成分的诱导。
