mPTP opening caused by Cdk5 loss is due to increased mitochondrial Ca²⁺ uptake.

We previously demonstrated that loss of Cdk5 in breast cancer cells promotes 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 Ca²⁺ 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 Ca²⁺ transfer from the ER to the mitochondria. Loss of Cdk5 also causes increased ATP-mediated mitochondrial Ca²⁺ uptake from the ER. Inhibition of ER Ca²⁺ release or mitochondrial Ca²⁺ uptake in Cdk5^-/- MEFs prevents mPTP opening, indicating that mPTP opening in Cdk5^-/- MEFs is due to increased Ca²⁺ transfer from the ER to the mitochondria. Altogether, our findings suggest that Cdk5 in MAMs regulates mitochondrial Ca²⁺ homeostasis that is disturbed upon Cdk5 loss, which leads to mPTP opening.

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