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Updated: Mar 8, 2026
Multi-parameter Measurement of the Permeability Transition Pore Opening in Isolated Mouse Heart Mitochondria
Published on: September 7, 2012
Preventing permeability transition pore opening increases mitochondrial maturation, myocyte differentiation and
Jayson V Lingan1,2, Ryan E Alanzalon2, George A Porter2,3,4
1Current affiliation: Department of Pediatrics, Benefits Health System, Great Falls, Montana.
Insights
Inhibiting the mitochondrial permeability transition pore (PTP) regulator, cyclophilin D (CyPD), in neonatal cardiac myocytes promotes mitochondrial maturation and enhances cardiac function. This suggests potential therapeutic strategies for improving heart health in newborns.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Neonatal Physiology
Background:
- Mitochondrial permeability transition pore (PTP) closure is crucial for embryonic myocyte maturation and differentiation.
- Neonatal cardiac myocytes are immature, presenting a window for therapeutic intervention.
- Cyclophilin D (CyPD) regulates PTP opening and is a potential therapeutic target.
Purpose of the Study:
- To investigate if inhibiting CyPD in neonatal cardiac myocytes enhances mitochondrial maturation and cardiac function.
- To determine the effects of PTP inhibition on myocyte differentiation and overall cardiac performance.
Main Methods:
- Neonatal myocytes and mice were treated with PTP inhibitors (CsA, NIM811) or vehicle.
- Mitochondrial function, structure, and myocyte differentiation were assessed in vitro.
- Cardiac function was evaluated in vivo using echocardiography in treated mice.
Main Results:
- PTP inhibition increased mitochondrial complexity, membrane potential, and myocyte differentiation in vitro.
- Neonatal mice treated with PTP inhibitors exhibited improved ejection fractions.
- Genetic deletion of CyPD mirrored the beneficial effects of pharmacological inhibition.
Conclusions:
- Inhibiting the PTP in neonates is a feasible strategy to promote mitochondrial maturation.
- Pharmacological PTP inhibition can enhance cardiac myocyte differentiation and improve cardiac function in newborns.
- Targeting CyPD offers a potential therapeutic approach for neonatal cardiac health.
Background:
In embryonic myocytes, closure of the mitochondrial permeability transition pore (PTP) drives mitochondrial maturation and cardiac myocyte differentiation. Since neonatal cardiac myocytes remain relatively immature, we hypothesized that inducing PTP closure at this age, by inhibiting the PTP regulator, cyclophilin D (CyPD), genetically or with Cyclosporin A (CsA) and NIM811, would increase cardiac function by increasing mitochondrial maturation and myocyte differentiation.
Methods:
Cultured neonatal myocytes or neonatal mice were treated for 5 d with vehicle, CsA or NIM811. Mitochondrial function and structure were measured in vitro. Myocyte differentiation was assessed by immunolabeling for contractile proteins. Cardiac function was determined using echocardiography.
Results:
The probability of PTP opening was high in WT neonatal myocytes. Treatment with CsA or NIM811 in vitro increased mitochondrial structural complexity and membrane potential, decreased reactive oxygen species levels, and increased myocyte differentiation. WT mice treated with either CsA or NIM811 in vivo for the first 5 d of life had higher ejection fractions. Deleting CyPD had similar effects as CsA and NIM811 on all parameters.
Conclusions:
It may be feasible to inhibit the PTP using available drugs to increase mitochondrial maturation, myocyte differentiation, and cardiac function in neonates.
