Shi Han, Deng Han-Xiang, Gius David, Schumacker Paul T, Surmeier D James, Ma Yong-Chao
Departments of Pediatrics, Neurology and Physiology, Northwestern University Feinberg School of Medicine, Anne & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
The Ken & Ruth Davee Department of Neurology.
Hum Mol Genet. 2017 May 15;26(10):1915-1926. doi: 10.1093/hmg/ddx100.
Age-dependent elevation in mitochondrial oxidative stress is widely posited to be a major factor underlying the loss of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease (PD). However, mechanistic links between aging and oxidative stress are not well understood. Sirtuin-3 (Sirt3) is a mitochondrial deacetylase that could mediate this connection. Indeed, genetic deletion of Sirt3 increased oxidative stress and decreased the membrane potential of mitochondria in SNc dopaminergic neurons. This change was attributable to increased acetylation and decreased activity of manganese superoxide dismutase (MnSOD). Site directed mutagenesis of lysine 68 to glutamine (K68Q), mimicking acetylation, decreased MnSOD activity in SNc dopaminergic neurons, whereas mutagenesis of lysine 68 to arginine (K68R), mimicking deacetylation, increased activity. Introduction of K68R MnSOD rescued mitochondrial redox status and membrane potential of SNc dopaminergic neurons from Sirt3 knockouts. Moreover, deletion of DJ-1, which helps orchestrate nuclear oxidant defenses and Sirt3 in mice led to a clear age-related loss of SNc dopaminergic neurons. Lastly, K68 acetylation of MnSOD was significantly increased in the SNc of PD patients. Taken together, our studies suggest that an age-related decline in Sirt3 protective function is a major factor underlying increasing mitochondrial oxidative stress and loss of SNc dopaminergic neurons in PD.
线粒体氧化应激随年龄增长而升高，普遍认为这是帕金森病（PD）中黑质致密部（SNc）多巴胺能神经元丢失的主要因素。然而，衰老与氧化应激之间的机制联系尚未完全明确。沉默调节蛋白3（Sirt3）是一种线粒体去乙酰化酶，可能介导这种联系。事实上，Sirt3基因缺失会增加氧化应激，并降低SNc多巴胺能神经元的线粒体膜电位。这种变化归因于锰超氧化物歧化酶（MnSOD）的乙酰化增加和活性降低。将赖氨酸68定点突变为谷氨酰胺（K68Q），模拟乙酰化，会降低SNc多巴胺能神经元中的MnSOD活性，而将赖氨酸68突变为精氨酸（K68R），模拟去乙酰化，则会增加活性。引入K68R MnSOD可挽救Sirt3基因敲除小鼠SNc多巴胺能神经元的线粒体氧化还原状态和膜电位。此外，在小鼠中缺失有助于协调核抗氧化防御和Sirt3的DJ-1，会导致SNc多巴胺能神经元明显出现与年龄相关的丢失。最后，PD患者SNc中MnSOD的K68乙酰化显著增加。综上所述，我们的研究表明，Sirt3保护功能随年龄增长而下降是PD中线粒体氧化应激增加和SNc多巴胺能神经元丢失的主要因素。
