Reductions in the mitochondrial enzyme -ketoglutarate dehydrogenase complex in neurodegenerative disease - beneficial or detrimental?
Reductions in the mitochondrial enzyme -ketoglutarate dehydrogenase complex in neurodegenerative disease - beneficial or detrimental?
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DOI：
10.1111/jnc.13836
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发表时间：
2016-12-01
影响因子：
4.7
通讯作者：
Gibson, Gary E.
中科院分区：
文献类型：
--
作者：
Chen, Huanlian;Denton, Travis T.;Gibson, Gary E.
代谢减少和过度氧化应激在多种神经退行性疾病中普遍存在。线粒体酶-酮戊二酸脱氢酶复合物（KGDHC）的活性似乎是这些异常的核心。KGDHC在多种神经退行性疾病中减少。KGDHC不仅可以限制NADH产生和底物水平磷酸化的速率，而且也是活性氧（ROS）的来源。这些研究的目的是确定KGDHC的变化如何改变基线ROS、缓冲ROS的能力、基线谷胱甘肽化、钙调节和响应于外部氧化剂的细胞死亡。在体内，用腺病毒减少KGDHC会减少神经发生并增加氧化应激。在体外，短时间的治疗增加了ROS和谷胱甘肽化，并增强了细胞从添加的氧化剂中减少ROS的能力。然而，长期减少降低了减少ROS的能力，减少了谷胱甘肽化，夸大了氧化剂诱导的钙变化和细胞死亡。增加KGDHC增强了细胞减少外部添加的ROS的能力，并防止氧化剂诱导的钙变化和细胞死亡。结果表明，短期减少KGDHC是保护，而长期减少是有害的。此外，升高的KGDHC活性具有保护作用。因此，增加KGDHC的促有丝分裂疗法可能对神经退行性疾病有益。
Reductions in metabolism and excess oxidative stress are prevalent in multiple neurodegenerative diseases. The activity of the mitochondrial enzyme -ketoglutarate dehydrogenase complex (KGDHC) appears central to these abnormalities. KGDHC is diminished in multiple neurodegenerative diseases. KGDHC can not only be rate limiting for NADH production and for substrate level phosphorylation, but is also a source of reactive oxygen species (ROS). The goal of these studies was to determine how changes in KGDHC modify baseline ROS, the ability to buffer ROS, baseline glutathionylation, calcium modulation and cell death in response to external oxidants. In vivo, reducing KGDHC with adeno virus diminished neurogenesis and increased oxidative stress. In vitro, treatments of short duration increased ROS and glutathionylation and enhanced the ability of the cells to diminish the ROS from added oxidants. However, long-term reductions lessened the ability to diminish ROS, diminished glutathionylation and exaggerated oxidant-induced changes in calcium and cell death. Increasing KGDHC enhanced the ability of the cells to diminish externally added ROS and protected against oxidant-induced changes in calcium and cell death. The results suggest that brief periods of diminished KGDHC are protective, while prolonged reductions are harmful. Furthermore, elevated KGDHC activities are protective. Thus, mitogenic therapies that increase KGDHC may be beneficial in neurodegenerative diseases.