2. Academic Validation
  3. Ca2+-mediated mitochondrial inner membrane permeabilization induces cell death independently of Bax and Bak

Ca2+-mediated mitochondrial inner membrane permeabilization induces cell death independently of Bax and Bak

  • Cell Death Differ. 2022 Jul;29(7):1318-1334. doi: 10.1038/s41418-022-01025-9.
Giovanni Quarato 1,  Fabien Llambi 2 3,  Cliff S Guy 2,  Jaeki Min 4 5,  Marisa Actis 4,  Huan Sun 6,  Shilpa Narina 7,  Shondra M Pruett-Miller 7,  Junmin Peng 6,  Zoran Rankovic 4,  Douglas R Green 8
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. giovanni.quarato@stjude.org.
  • 2 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 3 Relay Therapeutics, Cambridge, MA, 02139, USA.
  • 4 Department of Chemical Biology & Therapeutic, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 5 Amgen Inc., Thousand Oaks, CA, 91320, USA.
  • 6 Department of Structural Biology, Department of Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 7 Department of Cell and Molecular Biology and The Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 8 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. douglas.green@stjude.org.
PMID: 35726022 DOI: 10.1038/s41418-022-01025-9
Abstract

The ability of mitochondria to buffer a rapid rise in cytosolic CA2+ is a hallmark of proper cell homeostasis. Here, we employed m-3M3FBS, a putative Phospholipase C (PLC) agonist, to explore the relationships between intracellular CA2+ imbalance, mitochondrial physiology, and cell death. m-3M3FBS induced a potent dose-dependent CA2+ release from the endoplasmic reticulum (ER), followed by a rise in intra-mitochondrial CA2+. When the latter exceeded the organelle buffering capacity, an abrupt mitochondrial inner membrane permeabilization (MIMP) occurred, releasing matrix contents into the cytosol. MIMP was followed by cell death that was independent of Bcl-2 Family members and inhibitable by the intracellular CA2+ chelator BAPTA-AM. Cyclosporin A (CsA), capable of blocking the mitochondrial permeability transition (MPT), completely prevented cell death induced by m-3M3FBS. However, CsA acted upstream of mitochondria by preventing CA2+ release from ER stores. Therefore, loss of CA2+ intracellular balance and mitochondrial CA2+ overload followed by MIMP induced a cell death process that is distinct from Bcl-2 family-regulated mitochondrial outer membrane permeabilization (MOMP). Further, the inhibition of cell death by CsA or its analogues can be independent of effects on the MPT.

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