Protectors of the Mitochondrial Permeability Transition Pore Activated by Iron and Doxorubicin

(E-pub Ahead of Print)

Author(s): Tatiana A. Fedotcheva, Nadezhda I. Fedotcheva*

Journal Name: Current Cancer Drug Targets


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Abstract:

Aim: The study is aimed at examining of action of iron, DOX, and their complex on the mitochondrial permeability transition pore (MPTP) opening and detecting of possible protectors of MPTP in the conditions close to mitochondria-dependent ferroptosis.

Background: The toxicity of doxorubicin (DOX) is mainly associated with free iron accumulation and mitochondrial dysfunction. DOX can provoke ferroptosis, iron-dependent cell death driven by membrane damage. The mitochondrial permeability transition pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. The influence of DOX on the Ca2+ -induced MPTP opening in the presence of iron has not yet been studied.

Objective: The study was conducted on isolated liver and heart mitochondria. MPTP and succinate- ubiquinone oxidoreductase were studied as targets of DOX in mitochondria-dependent ferroptosis. The iron chelator deferoxamine (DFO), the lipid radical scavenger butyl-hydroxytoluene (BHT), and rutenium red (Rr), as a possible inhibitor of ferrous ions uptake in mitochondria, were tested as MPTP protectors. The role of medium alkalization was also examined.

Methods: Changes of threshold calcium concentrations required for MPTP opening were measured by a Ca2+ selective electrode, mitochondrial membrane potential was registered by tetraphenylphosphonium (TPP+)-selective electrode, and mitochondrial swelling was recorded as a decrease in absorbance at 540 nm. The activity of succinate dehydrogenase (SDH) was determined by the reduction of the electron acceptor DCPIP.

Conclusion: MPTP and the respiratory complex II are identified as the main targets of the iron-dependent action of DOX on the isolated mitochondria. All MPTP protectors tested abolished or weakened the effect of iron and a complex of iron with DOX on Ca2+ -induced MPTP opening, acting in different stages of MPTP activation. These data open new approaches to the modulation of the toxic influence of DOX on mitochondria with the aim to reduce their dysfunction.

Keywords: Doxorubicin, iron, mitochondrial permeability transition pore, butylhydroxytoluene, alkalization, deferoxamine.

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Article Details

(E-pub Ahead of Print)
DOI: 10.2174/1568009621999210120192558
Price: $95

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