| First Author | NavaneethaKrishnan S | Year | 2020 |
| Journal | Oncogene | Volume | 39 |
| Issue | 13 | Pages | 2797-2806 |
| PubMed ID | 32024968 | Mgi Jnum | J:299432 |
| Mgi Id | MGI:6490860 | Doi | 10.1038/s41388-020-1188-5 |
| Citation | NavaneethaKrishnan S, et al. (2020) mPTP opening caused by Cdk5 loss is due to increased mitochondrial Ca(2+) uptake. Oncogene 39(13):2797-2806 |
| abstractText | We previously demonstrated that loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death by inducing mitochondrial permeability transition pore (mPTP) opening (Oncogene 37, 1788-1804). However, the molecular mechanism by which Cdk5 loss causes mPTP opening remains to be investigated. Using primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5(-/-) mouse embryos, we show that absence of Cdk5 causes a significant increase in both mPTP opening and mitochondrial Ca(2+) level. Analysis of subcellular fractions of MEFs demonstrates that Cdk5 localizes in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and Cdk5 loss in MAMs causes increased ER-mitochondria tethering, a process required for Ca(2+) transfer from the ER to the mitochondria. Loss of Cdk5 also causes increased ATP-mediated mitochondrial Ca(2+) uptake from the ER. Inhibition of ER Ca(2+) release or mitochondrial Ca(2+) uptake in Cdk5(-/-) MEFs prevents mPTP opening, indicating that mPTP opening in Cdk5(-/-) MEFs is due to increased Ca(2+) transfer from the ER to the mitochondria. Altogether, our findings suggest that Cdk5 in MAMs regulates mitochondrial Ca(2+) homeostasis that is disturbed upon Cdk5 loss, which leads to mPTP opening. |
