El-Khoury Riyad, Kaulio Eveliina, Lassila Katariina A, Crowther Damian C, Jacobs Howard T, Rustin Pierre
INSERM UMR 1141 and Université Paris 7, Faculté de Médecine Denis Diderot, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France; American University of Beirut Medical Center, Department of Pathology and Laboratory Medicine, Cairo Street, Hamra, Beirut, Lebanon.
BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
Free Radic Biol Med. 2016 Jul;96:57-66. doi: 10.1016/j.freeradbiomed.2016.04.006. Epub 2016 Apr 14.
Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease.
线粒体功能障碍与阿尔茨海默病的病理过程广泛相关，但对于它是疾病的原因还是结果，以及确切的机制，尚无共识。我们通过在不同的阿尔茨海默病病理模型中测试表达来自玻璃海鞘的交替氧化酶AOX的效果，来解决这些问题。当线粒体呼吸链的细胞色素部分受到抑制时，AOX可以恢复呼吸电子流，支持ATP合成，维持细胞氧化还原稳态，并减轻呼吸复合体I和III处过量的超氧化物产生。在源自人类HEK293的细胞中，AOX的表达减少了抗霉素抑制呼吸复合体III所导致的β-淀粉样肽的产生。由于过氧化氢既不是AOX的直接产物也不是底物，因此AOX在该试验中模拟抗氧化剂的能力必定是间接的。此外，AOX的表达能够部分缓解神经元表达人类β-淀粉样肽的果蝇模型的短寿命，同时消除氧化应激标志物的诱导。我们的研究结果支持呼吸链功能障碍和过量ROS产生既是阿尔茨海默病发病机制的早期步骤，也是具有病理意义的靶点这一观点，支持了该疾病潜在的线粒体恶性循环的概念。
