Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy.
Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
Oxid Med Cell Longev. 2019 Oct 31;2019:4721950. doi: 10.1155/2019/4721950. eCollection 2019.
Several neurodegenerative disorders exhibit selective vulnerability, with subsets of neurons more affected than others, possibly because of the high expression of an altered gene or the presence of particular features that make them more susceptible to insults. On the other hand, resilient neurons may display the ability to develop antioxidant defenses, particularly in diseases of mitochondrial origin, where oxidative stress might contribute to the neurodegenerative process. In this work, we investigated the oxidative stress response of embryonic fibroblasts and cortical neurons obtained from -KO mice. encodes a subunit of a protease complex that is expressed in mitochondria and acts as both quality control and regulatory enzyme affecting respiration and mitochondrial dynamics. When cells were subjected to an acute oxidative stress protocol, the survival of AFG3L2-KO MEFs was not significantly influenced and was comparable to that of WT; however, the basal level of the antioxidant molecule glutathione was higher. Indeed, glutathione depletion strongly affected the viability of KO, but not of WT MEF, thereby indicating that oxidative stress is more elevated in KO MEF even though well controlled by glutathione. On the other hand, when cortical KO neurons were put in culture, they immediately appeared more vulnerable than WT to the acute oxidative stress condition, but after few days in vitro, the situation was reversed with KO neurons being more resistant than WT to acute stress. This compensatory, protective competence was not due to the upregulation of glutathione, rather of two mitochondrial antioxidant proteins: superoxide dismutase 2 and, at an even higher level, peroxiredoxin 3. This body of evidence sheds light on the capability of neurons to activate neuroprotective pathways and points the attention to peroxiredoxin 3, an antioxidant enzyme that might be critical for neuronal survival also in other disorders affecting mitochondria.
几种神经退行性疾病表现出选择性易损性，部分神经元比其他神经元更容易受到影响，这可能是由于异常基因的高表达或某些特征的存在，使它们更容易受到损伤。另一方面，有弹性的神经元可能表现出发展抗氧化防御的能力，特别是在起源于线粒体的疾病中，氧化应激可能有助于神经退行性过程。在这项工作中，我们研究了从 -/- 小鼠获得的胚胎成纤维细胞和皮质神经元的氧化应激反应。 编码一种蛋白酶复合物的亚基，该蛋白酶复合物在线粒体中表达，作为质量控制和调节酶，影响呼吸和线粒体动力学。当细胞受到急性氧化应激方案处理时，AFG3L2-KO MEF 的存活率没有明显受到影响，与 WT 相当；然而，抗氧化分子谷胱甘肽的基础水平较高。事实上，谷胱甘肽耗竭强烈影响 KO，但不影响 WT MEF 的活力，从而表明 KO MEF 中的氧化应激水平更高，尽管通过谷胱甘肽得到很好的控制。另一方面，当皮质 KO 神经元被放入培养物中时，它们立即比 WT 神经元对急性氧化应激条件更脆弱，但在体外几天之后，情况发生逆转，KO 神经元比 WT 神经元对急性应激更具抵抗力。这种代偿性的保护能力不是由于谷胱甘肽的上调，而是由于两种线粒体抗氧化蛋白：超氧化物歧化酶 2 和更高水平的过氧化物酶 3。这一证据表明神经元激活神经保护途径的能力，并引起人们对过氧化物酶 3 的关注，过氧化物酶 3 是一种抗氧化酶，在影响线粒体的其他疾病中对神经元存活也可能至关重要。
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