Affiliation:
1. Science Research Laboratory of Pharmacology, Faculty of Medical Biology, N. I. Pirogov Russian National Medical Research University, Ministry of Health of the Russian Federation, Moscow, Russian Federation
2. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region, 142290, Russian Federation
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.
Funder
Russian Foundation for Basic Research
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Drug Discovery,Pharmacology,Oncology
Cited by
17 articles.
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