PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online)
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Physiol. Res. 61 (Suppl. 1): S165-S172, 2012
Developmental Changes of the Sensitivity of Cardiac and Liver
Mitochondrial Permeability Transition Pore to Calcium Load
and Oxidative Stress
Z. DRAHOTA1,2,3, M. MILEROVÁ1,2, R. ENDLICHER3, D. RYCHTRMOC3,
Z. ČERVINKOVÁ3, B. OŠŤÁDAL1,2
1Centre for Cardiovascular Research, Prague, Czech Republic, 2Institute of Physiology, Academy of
Sciences of the Czech Republic, 3Department of Physiology, Faculty of Medicine in Hradec
Králové, Charles University, Prague, Czech Republic
Received April 17, 2012
Accepted May 31, 2012
Opening of the mitochondrial membrane permeability transition
pore (MPTP) is an important factor in the activation of apoptotic
and necrotic processes in mammalian cells. In a previous paper
we have shown that cardiac mitochondria from neonatal rats are
more resistant to calcium load than mitochondria from adult
animals. In this study we have analyzed the ontogenetic
development of this parameter both in heart and in liver
mitochondria. We found that the high resistance of heart
mitochondria decreases from day 14 to adulthood. On the other
hand, we did not observe a similar age-dependent sensitivity in
liver mitochondria, particularly in the neonatal period. Some
significant but relatively smaller increase could be observed only
after day 30. When compared with liver mitochondria cardiac
mitochondria were more resistant also to the peroxide activating
effect on calcium-induced mitochondrial swelling. These data
thus indicate that the MPTP of heart mitochondria is better
protected against damaging effects of the calcium load and
oxidative stress. We can only speculate that the lower sensitivity
to calcium-induced swelling may be related to the higher
ischemic tolerance of the neonatal heart.
MPTP • Developmental and tissue specificity • Cardiac
mitochondria • Liver mitochondria • Calcium load • Oxidative
stress • Rat
B. Ošťádal, Institute of Physiology, Academy of Sciences of the
Czech Republic, Vídeňská 1083, Prague 4, Czech Republic.
Cardiac resistance of the immature heart to
oxygen deficiency is significantly higher as compared
with the adult myocardium. However, the mechanisms of
the higher resistance have not yet been satisfactorily
clarified (Ostadal et al. 2009, 2011). Still unclear is the
role of mitochondria in the developmental changes of
cardiac tolerance to oxygen deprivation, in spite of the
fact that mitochondria are responsible for cellular oxygen
handling. The opening
mitochondrial permeability transition pore (MPTP) has
been implicated in the molecular mechanisms associated
with ischemia/reperfusion (I/R) injury of the adult heart
(Di Lisa and Bernardi 1998, Rasola and Bernardi 2011).
We observed, however,
differences in the role of MPTP in the I/R injury
(Milerova et al. 2010). In cardiac mitochondria isolated
from neonatal (7-day-old rats), calcium-dependent and
cyclosporine-sensitive MPTP is less sensitive to Ca2+ ions
as compared with adults (90-day-old rats). This suggests
that the neonatal cardiac mitochondria are better
protected against Ca-induced opening of the MPTP,
which is an important factor in the activation of apoptotic
and necrotic processes in mammalian cells (Rasola and
Bernardi 2011). We can only speculate that the lower
sensitivity to calcium-induced swelling may be related to
the higher ischemic tolerance of the neonatal heart
(Ostadal et al. 1999, 2009).
Since the cardiac
of a high-conductance
tolerance to oxygen
S166 Drahota et al.
deprivation significantly decreases during postnatal
ontogeny, it was of interest to ask whether the calcium
sensitivity of cardiac mitochondria exhibits similar
changes during postnatal development. To test this
hypothesis we have compared the results obtained
previously in neonatal and 90-day-old rats and we tested
cardiac mitochondria from hearts of 5-, 14-, 30-, and
60-day-old male rats. Considering that Panov et al.
(2007) and Endlicher et al. (2009) have observed that
mitochondria from different tissues of adult animals have
different sensitivity of MPTP to calcium ions, we wanted
to know to which extent the possible developmental
changes in the sensitivity of MPTP to calcium and ROS
activating effects are tissue-specific. For this comparison
we have used mitochondria from significantly different
tissues – heart and liver. It was demonstrated that
oxidative stress highly increases the sensitivity of the
MPTP to calcium (Kim et al. 2006). We have, therefore,
also compared the activating effect of ROS on
Ca-induced swelling in heart and liver mitochondria from
Materials and Methods
All experiments were performed on Wistar
male rats at different ontogenetic periods, critical for the
structural and functional development of cardiac
mitochondria: postnatal day 5 (neonatal period), day 14
(structural organization of cardiac mitochondria –
Ostadal and Schiebler 1971), day 30 (the end of
weaning period, development of mitochondrial enzymes
Skarka et al. 2003) and day 60 (sexual maturation). For
the isolation of heart and liver mitochondria from
5-day-old rats, 10-30 animals were used for one
preparation of mitochondria. From 14- and 30-day-old
rats organs from 3-5 animals were analyzed; from
60-day-old rats only one organ for one preparation was
used. Animals had free access to water and standard
laboratory diet. They were maintained on a 12-h
light/12-h dark cycle. All the investigations conform to
the Guide for the Care and Use of Laboratory Animals
(NIH publication No. 85-23, revised 1996).
All chemicals were of the highest commercially
available purity and were purchased from Sigma (Sigma
Aldrich Co., Germany).
Isolation of mitochondria from rat heart and liver
The animals were sacrificed by cervical
dislocation. The hearts were dissected free of atrial tissue
and large blood vessels. Tissue samples were cut and
homogenized at 0 °C by a teflon-glass homogenizer in a
medium containing 220 mM mannitol, 70 mM sucrose,
2 mM HEPES, 0.2 mM EGTA, 0.5 mg bovine serum
albumin/ml, pH 7.2. The homogenate (100 mg wet
wt/ml) was centrifuged for 10 min at 800 x g and the
resulting supernatant at 8000 x g. The mitochondrial
sediment was washed twice in the isolation medium
without BSA and EGTA for 10 min at 8000 x g and
suspended in the same medium. Liver mitochondria were
prepared under the same experimental conditions. Protein
concentration was determined by the Bredford method
(Bredford 1976) using BSA as a standard. Integrity of
each mitochondrial preparation
determination of the respiratory control index (RCI) using
OROBOROS-K2 high-resolution oxygraph (Pecinova et
al. 2011). Values of the RCI in the presence of glutamate
and malate were in heart mitochondrial preparations in
the range of 4-6 and in liver preparations in the range of
Measurement of mitochondrial swelling
Parameters of the mitochondrial swelling
process were measured as described in our previous
papers (Milerova et al. 2010, Drahota et al. 2012) with
minor modifications. Mitochondrial swelling was
estimated from the decrease of absorbance at 520 nm in a
Perkin Elmer Llambda2 spectrophotometer at 30 °C in a
swelling medium of 65 mM KCl, 125 mM sucrose,
65 mM KCl, 10 mM HEPES (pH7.2), 5 mM succinate
and 1 mM KPO4 (Castilho et al. 1998). Mitochondria
were added to provide the absorbance of about 1 (about
0.4 mg protein per ml). After one min of preincubation of
mitochondrial suspension, CaCl2 solution was added and
the absorbance changes were detected at 0.1 min intervals
for further 5 min. Two parameters of the swelling process
were evaluated: (a) the extent of swelling, (b) the
maximum swelling rate. The extent of swelling was
evaluated as the decrease of absorbance at 520 nm of the
mitochondrial suspension during 5 min after calcium
addition and expressed as A520 change/5 min. The
maximum swelling rate was calculated after derivation of
swelling curves and expressed as dA520/0.1min.
The data were expressed as means ± S.E.M.
was tested by
Resistance of Cardiac MPTP to Ca2+ and ROS S167
Differences among groups were analyzed by one-way
analysis of variance using Student-Newman-Keuls
multiple range test. Results were considered as
statistically significant when P≤0.05.
We have confirmed our previous results
suggesting age- and tissue specificity of the sensitivity of
mitochondria to Ca-induced swelling (Endlicher et al.
2009, Milerova et al. 2010) (Figs 1 and 2). In the present
experiments we have analyzed the time-course of the
ontogenetic development of the Ca-induced swelling rate
in heart mitochondria isolated from 5-, 14-, 30- and
60-day-old rats. We used 200 μM Ca2+ concentrations for
induction of swelling because it gives the maximum
values of the swelling rate (Milerova et al. 2010). We
observed that the low sensitivity of heart mitochondria to
the calcium load does not change till day 14 of postnatal
age; during the period between days 14 and 60 it
continuously increases (Table 1).
Table 1. The maximum swelling rate of the heart and liver
mitochondria isolated from 5-,14-,30-and 60-day-old rats.
Age (days) Heart Liver
Mitochondrial swelling was induced by 200 µM CaCl2 and the
swelling rate was expressed as dA520/0.1 min. Significance of
the increase was related to values of 5-day-old rats.
Fig. 1. The extent of swelling (A, C) and the
maximum swelling rate (B, D) of heart
mitochondria isolated from 5-day-old rats
(A, B). CaCl2 200 µM was added after 1 min
of preincubation of mitochondria as indicated.
The extent of swelling was calculated as the
decrease of absorbance at 520 nm during
5 min after addition of CaCl2. The value of
maximum swelling rate was obtained after
derivation of absorbency changes (A, C).
Calculation of swelling rates starts after
addition of CaCl2.
Fig. 2. The extent (A) and the maximum
swelling rate (B) of rat liver mitochondria
isolated from 60-day-old rats. Experimental
conditions and swelling rate calculation were
the same as in the Figure 1.
Extent of swelling (A520)
Extent of Sw elling (A52 0)
Rate of Swelling (dA520/0.1 min)
R ate of Swe lling (d A52 0/0.1 min )
Rate of Swelling ( dA520/0.1 min)
Rate = 0.0827/0.1min
Extent of Swelling (A520)
Extent = 0.428/5min
S168 Drahota et al.
Ontogenetic development of the sensitivity of
MPTP to calcium ions in liver mitochondria was
markedly different (Table 1). The values of the swelling
rate between postnatal days 14 and 30 did not increase as
in the heart mitochondria and the increase between
postnatal days 30 and 60 was significantly smaller
(Table 1). The difference between liver and heart
mitochondria is even more evident when we expressed
age-dependent swelling rates in both mitochondrial
preparations as percentage of maximum values obtained
in mitochondria isolated from 60-day-old rats (Fig. 3).
We have not observed
mitochondial swelling in heart and liver mitochondria
with Ca2+ concentrations above 200 μM (not shown).
Because the differences in the swelling rates
could result from mechanical structural properties of
particular mitochondrial membranes, we tested the
maximum capacity of mitochondrial swelling of heart and
liver mitochondria from 60-day-old rats using the
channel-forming antibiotic alamecitin (Gostimskaja et al.
2003, Panov et al. 2007). We found that the values of
permeability barrier in liver and heart mitochondria were
lower than those induced by maximum concentrations of
200 μM Ca2+ used in our experiments (Fig. 4, Table 1).
Similarly, swelling induced by hypotonic medium clearly
indicated that the observed differences between neonatal
and adult mitochondia are not the result of different
mechanical properties of the mitochondrial membranes
because in 10-times diluted swelling medium the
decrease of absorbance was the same in heart
mitochondria isolated from 5-day-old and 60-day-old rats
(not shown). In the heart mitochondria both the extent
and the rate of calcium-induced swelling was much lower
than in the liver mitochondria (Figs 1 and 2). This
difference was markedly pronounced in the concentration
range of 25-100 μM Ca2+. At concentrations close to
intracellular (5-10 μM), differences between heart and
liver mitochondria were not apparent (Fig. 5A).
ROS belong to the most effective agents that can
increase the sensitivity of MPTP to Ca2+ ions (Kim et al.
2006, Halestrap 2009). We tested, therefore, the
activation of Ca-induced
hydroperoxide (t-BHP) both in heart and liver
mitochondria; for this purpose we have used low calcium
concentrations giving very low rates of swelling (Fig. 5).
When we tested liver mitochondria from 5-day old rats at
5 μM calcium, we found very high activation of swelling
rate by 0.75 mM t-BHP (Fig. 6A). On the other hand, in
additional increase of
of the membrane
swelling by t-butyl
heart mitochondria from 5-day-old rats 0.75 mM t-BHP
was without any effect (data not shown). A small increase
in the swelling rate was observed only by increasing the
calcium concentration ten-fold to 50 μM and t-BHP four-
fold to 3 mM (Fig. 6B).
The major result of our experiments is the
finding that cardiac mitochondria of neonatal rats are
more resistant to calcium load as well as to the activating
effect of the oxidative stress as compared with neonatal
liver mitochondria. Moreover, this resistance significantly
decreases during postnatal ontogeny.
Mitochondria play an essential role in the
maintenance of intracellular calcium homeostasis and
MPTP represents one of the most important regulatory
factors (Carafoli 2010). The molecular structure of this
pore is very complicated. It is composed of proteins
localized on outer and inner mitochondrial membranes
and there are still discussions which of these proteins are
really necessary for its function (Walter et al. 2000,
Halestrap 2009, Carafoli 2010). In addition, the
mechanisms involved in the regulation of the opening and
closing the pore have not yet been fully elucidated. The
opening of the MPTP in the cardiac muscle was
Swelling rate (%60d-values)
Rat Heart Mito
Rat Liver Mito
Fig. 3. The maximum swelling rate induced by calcium in the
heart (RHM) and in liver (RLM) mitochondria isolated from
5-, 14-, 30- and 60-day-old rats. Data from Table 1 are
expressed in % of values obtained in liver (RLM) and heart
(RHM) mitochondria from 60-day-old rats.
Resistance of Cardiac MPTP to Ca2+ and ROS S169
suggested to play a decisive role in the pathogeny of I/R
injury (Di Lisa and Bernardi 1998, 2006). In this context
it was of interest to ask the question whether the role of
MPTP in the cardiac muscle changes during ontogenetic
development. Whereas the blockade of MPTP by
sanglifehrin in the adult perfused rat heart had a
protective effect on I/R injury damage, as already
demonstrated by Di Lisa et al. (2001), it had no effect in
neonatal heart (Milerova et al. 2010). For the explanation
of this difference a modified amount of cyclophilin
receptors in the neonatal heart or a lower sensitivity of
MPTP to pore opening factors have to be taken into
consideration. Our present data indicate that the
sensitivity of MPTP to the calcium induced swelling
changes significantly during ontogenetic development; it
is high in neonates and decreases from day 14 to
adulthood. These results suggest that the decreasing
tolerance to oxygen deprivation is accompanied by the
simultaneous increase of the sensitivity of cardiac
mitochondria to calcium-induced swelling.
In this context it is necessary to mention that
also other functions of cardiac mitochondria are not
completely developed in the rat heart at birth. Cardiac
maturation during the first postnatal week is characterized
by increasing content and specific activity of cytochrome
c oxidase and enhanced flux of nucleotides across the
inner mitochondrial membrane (Schagger et al. 1995,
Drahota et al. 2004). We have shown previously (Skarka
et al. 2003) that the content of cytochromes in cardiac
mitochondria increases two-fold between birth and day
30, similarly as the expression of adenine nucleotide
translocase 1. Moreover, in newborn animals a single
population of mitochondria with relatively high
mitochondrial membrane potential (MMP) was observed.
Starting with the weaning period, a second population
with significantly lower MMP occurs. All these facts
support the hypothesis that cardiac mitochondria are
deeply involved in the regulation of cardiac tolerance to
oxygen deprivation during ontogenetic development.
There appear some data indicating that opening
of the pore resulting in mitochondrial swelling may differ
among mitochondria isolated from different tissues and
also among mitochondria from various species (Richelli
et al. 2005, Panov et al. 2007, Endlicher et al. 2009). We
have observed significant
differences: the increase of the sensitivity to swelling
started in the liver mitochondria later (day 30) and the
final rise was smaller than in the heart mitochondria. We
did not follow longer periods than 60 days because the
swelling rate between 5 and 60 day-old rats was similar
Fig. 4. The decrease of the
absorbance changes in the heart
(A) and in liver (B) mitochondria
from adult rats induced by
Alamecitin (Ala - 1 µg/ml) was
0 50100150 200250
Ca μ μM
Swelling rate (dA520/0.1min)
Fig. 5. Calcium-induced swelling in the heart and in liver
mitochondria isolated from 60-day-old rats. Mitochondrial
swelling was induced by addition of 5, 12.5, 50, 100 and 200 µM
CaCl2. Data presented are the average from three experiments.
S170 Drahota et al.
to that we observed in 90-day-old rats (Milerova et al.
2010). The increased Ca-induced swelling rate was
observed only in the heart of 25 month-old rats (Petrosilo
et al. 2010), and in brain and liver mitochondria from
20-month-old rats (Mather and Rottenberg 2000).
Experiments with t-BHP have shown that also oxidative
stress has an important role in the activation of the
swelling process particularly at calcium concentrations
close to the values present in the cytosol under
physiological conditions; also these changes were age-
differences in the activating effects of calcium and
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(Basso et al. 2005, Elrod et al. 2010); similarly the
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dependent (Baines et al. 2005, Nakagawa et al. 2005,
Hafner et al. 2010, Lee et al. 2010). Developmental- and
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Conflict of Interest
There is no conflict of interest.
This work was supported by research projects RVO:
679 85823, by grant from Czech Science Foundation
303/12/1162 and PRVOUK, Faculty of Medicine in
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