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Updated: Dec 29, 2025

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
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Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess

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

Saranya NavaneethaKrishnan1, Jesusa L Rosales1, Ki-Young Lee2

  • 1Departments of Cell Biology and Anatomy, Arnie Charbonneau Cancer Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Oncogene
|February 7, 2020
PubMed

Insights

Loss of Cdk5 (cyclin-dependent kinase 5) in cells increases mitochondrial calcium levels, leading to the opening of the mitochondrial permeability transition pore (mPTP) and cell death.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Cancer Research

Background:

  • Previous work showed Cdk5 (cyclin-dependent kinase 5) loss in breast cancer cells induces ROS-mediated cell death via mPTP opening.
  • The precise molecular mechanism linking Cdk5 loss to mPTP opening was not understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which Cdk5 loss leads to mitochondrial permeability transition pore (mPTP) opening.
  • To investigate the role of Cdk5 in regulating mitochondrial calcium homeostasis.

Main Methods:

  • Primary mouse embryonic fibroblasts (MEFs) from Cdk5 knockout embryos were used.
  • Subcellular fractionation analyzed Cdk5 localization and its impact on ER-mitochondria contact sites (MAMs).
  • Mitochondrial calcium levels and ATP-mediated calcium uptake were measured.

Main Results:

  • Cdk5 deficiency significantly increased mPTP opening and mitochondrial Ca2+ levels in MEFs.
  • Cdk5 was found to localize in the mitochondria-associated ER membrane (MAM).
  • Loss of Cdk5 in MAMs enhanced ER-mitochondria tethering and ATP-mediated mitochondrial Ca2+ uptake.

Conclusions:

  • Cdk5 loss disrupts mitochondrial calcium homeostasis by increasing ER-mitochondria Ca2+ transfer.
  • This dysregulated calcium transfer leads to increased mPTP opening and cell death.
  • Cdk5 in MAMs is crucial for maintaining mitochondrial calcium balance.

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