| First Author | Byun J | Year | 2015 |
| Journal | Cell Death Differ | Volume | 22 |
| Issue | 6 | Pages | 959-73 |
| PubMed ID | 25361083 | Mgi Jnum | J:258839 |
| Mgi Id | MGI:6141213 | Doi | 10.1038/cdd.2014.184 |
| Citation | Byun J, et al. (2015) CR6-interacting factor 1 is a key regulator in Abeta-induced mitochondrial disruption and pathogenesis of Alzheimer's disease. Cell Death Differ 22(6):959-73 |
| abstractText | Mitochondrial dysfunction, often characterized by massive fission and other morphological abnormalities, is a well-known risk factor for Alzheimer''s disease (AD). One causative mechanism underlying AD-associated mitochondrial dysfunction is thought to be amyloid-beta (Abeta), yet the pathways between Abeta and mitochondrial dysfunction remain elusive. In this study, we report that CR6-interacting factor 1 (Crif1), a mitochondrial inner membrane protein, is a key player in Abeta-induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were downregulated in the pathological regions of Tg6799 mice brains, wherein overexpressed Abeta undergoes self-aggregation. Downregulation of Crif1 was similarly observed in human AD brains as well as in SH-SY5Y cells treated with Abeta. In addition, knockdown of Crif1, using RNA interference, induced mitochondrial dysfunction with phenotypes similar to those observed in Abeta-treated cells. Conversely, Crif1 overexpression prevented Abeta-induced mitochondrial dysfunction and cell death. Finally, we show that Abeta-induced downregulation of Crif1 is mediated by enhanced reactive oxygen species (ROS) and ROS-dependent sumoylation of the transcription factor specificity protein 1 (Sp1). These results identify the ROS-Sp1-Crif1 pathway to be a new mechanism underlying Abeta-induced mitochondrial dysfunction and suggest that ROS-mediated downregulation of Crif1 is a crucial event in AD pathology. We propose that Crif1 may serve as a novel therapeutic target in the treatment of AD. |
