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Updated: May 7, 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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Point of No Return-What Is the Threshold of Mitochondria With Permeability Transition in Cells to Trigger Cell Death

Kristina A Kritskaya1, Olga A Stelmashchuk2, Andrey Y Abramov2,3

  • 1Institute of Cell Biophysics of the Russian Academy of Sciences, Puschino, Russia.

Journal of Cellular Physiology
|January 6, 2025
PubMed

Insights

The number of mitochondria triggering cell death varies by tissue type. This threshold for apoptosis induction correlates with the balance of pro- and anti-apoptotic proteins, not just their total levels.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Physiology

Background:

  • Programmed cell death (apoptosis) is crucial for tissue regeneration and implicated in pathology.
  • Mitochondrial outer membrane permeabilization via the permeability transition pore (mPTP) releases pro-apoptotic factors, initiating apoptosis.
  • The precise threshold of mitochondria with mPTP opening for cell death induction and its tissue-specific regulation remain unclear.

Purpose of the Study:

  • To determine the number of mitochondria with mPTP opening required to induce apoptosis across different cell types.
  • To investigate the relationship between mPTP opening, cell death induction, and the expression of apoptosis-regulating proteins.
  • To explore the role of mPTP opening in calcium-induced necrosis.

Main Methods:

  • Simultaneous measurement of mitochondrial membrane potential and caspase-3 activation using fluorescent markers.
  • Induction of mPTP opening using calcium in primary rat cortical neurons, astrocytes, fibroblasts, and BT-474 cancer cells.
  • Quantification of mitochondria with mPTP opening and correlation with apoptosis and necrosis markers.

Main Results:

  • Apoptosis induction correlated with 80-90% mitochondrial signal loss in neural cells, 35% in fibroblasts, and >90% in BT-474 cells.
  • The number of mitochondria with mPTP opening required for cell death correlated with the Bax/Bcl-2 ratio, not total proapoptotic protein levels.
  • Calcium-induced mPTP opening led to higher necrosis levels in fibroblasts compared to other cell types.

Conclusions:

  • Different tissues exhibit distinct thresholds for mPTP opening to trigger apoptosis.
  • The Bax/Bcl-2 ratio is a key determinant of sensitivity to mPTP-induced apoptosis.
  • Tissue-specific regulation of mPTP opening influences both apoptosis and necrosis pathways.
Keywords:
apoptosisastrocytescaspase‐3fibroblastsmPTPmitochondrianecrosisneurons

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