Lunnon Katie, Keohane Aoife, Pidsley Ruth, Newhouse Stephen, Riddoch-Contreras Joanna, Thubron Elisabeth B, Devall Matthew, Soininen Hikka, Kłoszewska Iwona, Mecocci Patrizia, Tsolaki Magda, Vellas Bruno, Schalkwyk Leonard, Dobson Richard, Malik Afshan N, Powell John, Lovestone Simon, Hodges Angela
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; University of Exeter Medical School, University of Exeter, Devon, UK.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Neurobiol Aging. 2017 May;53:36-47. doi: 10.1016/j.neurobiolaging.2016.12.029. Epub 2017 Jan 7.
Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species.
尽管线粒体功能障碍是阿尔茨海默病在大脑和血液中的一个一致特征，但这些现象背后的分子机制尚不清楚。在这里，我们重复了我们之前的发现，即阿尔茨海默病和轻度认知障碍患者血液中核编码的氧化磷酸化（OXPHOS）亚基以及线粒体编码的OXPHOS基因翻译所需亚基的表达降低。有趣的是，这伴随着一些线粒体编码的OXPHOS基因表达增加，即那些最靠近多顺反子重链线粒体转录本（MT-ND1、MT-ND2、MT-ATP6、MT-CO1、MT-CO2、MT-C03）转录起始位点的基因以及从轻链转录的MT-ND6。此外，我们表明线粒体DNA拷贝数没有变化，这表明线粒体的稳态数量没有改变。我们认为，核基因组和线粒体基因组编码的OXPHOS转录本失衡可能会驱动一个负反馈回路，减少线粒体翻译并损害OXPHOS效率，这可能会产生有害的活性氧。
