Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines
Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines
复制标题
DOI：
10.1093/hmg/ddt247
复制
发表时间：
2013-10-01
影响因子：
3.5
通讯作者：
Swerdlow, Russell H.
中科院分区：
文献类型：
--
作者：
Silva, Diana F.;Selfridge, J. Eva;Swerdlow, Russell H.
生物能功能障碍发生在阿尔茨海默病 (AD) 和轻度认知障碍 (MCI) 中，后者是一种经常先于症状性 AD 发生的临床综合征。在这项研究中，我们通过将线粒体从 MCI、AD 和对照受试者血小板转移到 mtDNA 耗尽的 SH-SY5Y 细胞来模拟 AD 和 MCI 生物能功能障碍。在所得的细胞质杂种（cybrid）细胞系中表征了生物能通量和生物能学相关基础设施。相对于对照杂种，AD 和 MCI 杂种在耗氧量、呼吸耦合和葡萄糖利用方面表现出变化。 AD和MCI杂种具有较高的ADP/ATP和较低的NAD(+)/NADH比率。 AD 和 MCI 杂种在监测、响应或调节细胞生物能通量的蛋白质方面表现出差异，包括 HIF1 α、PGC1 α、SIRT1、AMPK、p38 MAPK 和 mTOR。几个终点表明，AD 杂种组中线粒体质量增加，而 MCI 杂种组中线粒体质量可能有所增加，并且 AD 和 MCI 杂种中线粒体裂变-融合平衡转向裂变增加。由于我们在 AD 和 MCI cybrid 模型中观察到的许多变化也出现在 AD 受试者的大脑中，因此我们得出的结论是，在 AD 的早期阶段就存在生物能量功能的降低，这不是大脑限制的，并且会引起千变万化的逆行反应，可能会产生适应性和适应不良的后果。
Bioenergetic dysfunction occurs in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a clinical syndrome that frequently precedes symptomatic AD. In this study, we modeled AD and MCI bioenergetic dysfunction by transferring mitochondria from MCI, AD and control subject platelets to mtDNA-depleted SH-SY5Y cells. Bioenergetic fluxes and bioenergetics-related infrastructures were characterized in the resulting cytoplasmic hybrid (cybrid) cell lines. Relative to control cybrids, AD and MCI cybrids showed changes in oxygen consumption, respiratory coupling and glucose utilization. AD and MCI cybrids had higher ADP/ATP and lower NAD(+)/NADH ratios. AD and MCI cybrids exhibited differences in proteins that monitor, respond to or regulate cell bioenergetic fluxes including HIF1 alpha, PGC1 alpha, SIRT1, AMPK, p38 MAPK and mTOR. Several end-points suggested mitochondrial mass increased in the AD cybrid group and probably to a lesser extent in the MCI cybrid group, and that the mitochondrial fission-fusion balance shifted towards increased fission in the AD and MCI cybrids. As many of the changes we observed in AD and MCI cybrid models are also seen in AD subject brains, we conclude reduced bioenergetic function is present during very early AD, is not brain-limited and induces protean retrograde responses that likely have both adaptive and mal-adaptive consequences.