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Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
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Mitochondrial permeability transition pore: sensitivity to opening and mechanistic dependence on substrate
Thomas Briston1, Malcolm Roberts2, Sian Lewis2
1Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, UK. thomas_briston@eisai.net.
Scientific Reports
|September 7, 2017
Summary
Mitochondrial metabolic state influences the opening of the mitochondrial permeability transition pore (mPTP). Understanding how cellular metabolism affects mPTP opening is key to developing new therapies for diseases involving cell death.
Area of Science:
- Mitochondrial physiology
- Cellular homeostasis
- Biochemistry
Background:
- Mitochondrial calcium (Ca2+) uptake is vital for cellular Ca2+ homeostasis.
- Excessive mitochondrial Ca2+ and oxidative stress can trigger the opening of the mitochondrial permeability transition pore (mPTP).
- mPTP opening is a critical cell death pathway in various diseases, making its regulation a therapeutic target.
Purpose of the Study:
- To investigate how mitochondrial metabolic state impacts the likelihood and outcomes of mPTP opening.
- To elucidate the role of different respiratory substrates in modulating Ca2+-induced mPTP opening.
Main Methods:
- Isolated mitochondria were energized using NADH- or FADH2-linked substrates.
- Ca2+ retention capacity was measured using fluorescence-based analysis.
- Simultaneous measurements of mitochondrial Ca2+ handling, membrane potential, respiratory rate, and reactive oxygen species (ROS) production were performed.
Main Results:
- Succinate-induced, membrane potential-dependent reverse electron transfer sensitized mitochondria to mPTP opening.
- mPTP opening under succinate inhibited reverse electron transfer and reduced Complex I respiration due to NADH leakage.
- ROS generated at Complex III did not sensitize mitochondria to mPTP opening.
Conclusions:
- Cellular metabolic fluxes and the metabolic environment significantly influence mitochondrial functional responses to Ca2+ overload.
- The metabolic state dictates the sensitivity and consequences of mPTP opening.
- Targeting cellular metabolism may offer novel therapeutic strategies for diseases associated with mPTP dysfunction.
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