Mitochondria-rich cells in the skin
epithelium of Amphibia are individually separated with their apical pole
aligned towards the outer side of the epithelium. They are common in all
Amphibian species, they are rich with mitochondria and carbonic anhydrase and
in addition to H+secretion they participate mainly in chloride conductance
across the epithelium. These cells carry out various functions except sodium
transport that is carried out by the principal cells' compartment. Application
of agonists and amiloride affected separately the two ionic pathways. MR cells
distribute unevenness over the body surface, apparently in relation to water
conservation. Studies in two species during ontogenetic development have
revealed the gradual appearance of MR cells, and that Cl-and Na+ transports developed
separately and independent of each other. It is not clear how the principal
cells compartment and MR cells are related in relation to their transport
Development; Heterocellularity; KCl; Proton ATPase
The amphibian skin epithelium plays protective and
respiratory functions and is a primary osmoregulatory organ, in addition to the
kidneys and urinary bladder. The physiological and biophysical transport
properties of the epithelium have been studied extensively[1-6] and there is a fair description of its histology
and cellularcomposition [7,8].
The skin epithelium is multilayered and
heterocellular, a common characteristic of tight epithelia in general. It is
comprised of Principal (Pr) Cells’ compartment which is engaged typically in
the active uptake of Na+. Other transport pathways are
localized in the intercalated Mitochondria-Rich (MR) cells that are assumed to
be the site for anion uptake and H+secretion [5,6,9,10]. A separate, NaCl secretory mechanism,
based on secondary active Cl-transport, is located in the
dermal mucus skin glands [5,11]. The functional
relationships and precise role(s) of the amphibian skin MR cells are not yet
settled [1,5,10,12]. There are also similarly
analogous intercalated or carbonic anhydrase-rich cells in the mammalian kidney
and the turtle urinary bladder which are the sites of H+and
that are ouabain insensitive .
The study of amphibian skin MR cells has progressed considerably
in the past years [5,6,12] both biophysically
and morphologically. It includes the use of specific molecular probes,
antibodies and lectins, allowing for a more faithful address of structure-
function relation in the epithelium .The
purpose of the present appraisal is 1. A critical account of the structure of
the amphibian skin, both anurans and urodeles, 2. Examine the structure and
composition of the MR cells and their diverse functions and, 3. Analyze the
individual transport functions of the skin epithelium and integrate them into a
rationally consistent picture. As will come up in the following, all species
examined contain MR cellsin the skin, which in certain species contain a
selective Cl-conductance (GCl). Mostly,theskin of mature
and adult forms will be considered, but ontogenetic and developmental aspects
will also be discussed [14-17].It is remarkable that despite the presence
of MR cells in all species, activated GCl is found mostly in toads' skins and
only rarely inthose of frogs (i.e. Rana pipiens;
1.1. Epithelial Structure and Cell Asymmetry
The amphibian skin epithelium contains 3-5 cell
layers. The first layer at the bottom, the stratum germinativumlays on the
basement membrane that rests on the dermal supporting connective tissue that
contains blood vessels and the exocrine glands. The cells of the epithelial
layer divide at a constant rate , and the
cells move towards the outer surface of the epithelium. As the cells approach
their position at the outer surface of the epithelium, they acquire their
potential asymmetry , becoming the stratum
granulosum cells.These cells, denote also
first reacting cell layer (RCL; , are
connected through Tight Junctions (TJ) at their apical pole and form the outer,
polar integumental barrier of the skin epithelium. Moulting in the amphibian
skin epithelium is particular. The outer cell layer is sloughed as a single
layer at regular intervals (3-5 days). This process was studied in depth in
Copenhagen (19, etc.). It turned out as an intensive
dynamics that is hormonally controlled.Itinvolvescontinualdifferentiationofspecificchannels(particularly
at the apical face and Na+/K+ATPase in the
basolateral membranes) as was revealed naturally in moultingBufoviridis. Gland tubes and a few MR cells are lost at each cycle
of sloughing. The epithelium appears then as
a dynamic tissue, and its cells undergo extensive turnover 
The principal cells intercommunicate through gap
junctions, and form a functional syncytium 
The Mitochondria-Rich (MR) cells are excluded from this syncytium and are
singly and separately dispersed among the principal cells, at the outer surface
of the epithelium.
1.2. Morphology and Histology
Intercalated Mitochondria-Rich (MR) cells
occupy variable percentage of the outer sur- face of the epithelium, amounting
some 3-10% of the total epithelial cells surface [19,25].
The cells are flask shaped, asymmetric, and must differentiate before they
approach their position among the outer epithelial cells. Recent studies have
begun to shed light on aspects of cell biology and dynamics of these cells [12,26,27]. A few Merkel and sensory cells are also
found in the epithelium , but they do not participate
in transport processes.TheMRcellscontainagreatvarietyofcomponents,i.e.theyarerichinmitochondriaand
Carbonic Anhydrase (CA  and react apically
with anti H+-ATPase and antiband3 antibodies. They are
characteristically stained by silver, and accumulate methylene blue from the
serosal side. Different enzyme pictures were found in MR cells upon acclimation
in 3 environmental conditions - NaCl, KCl and distilled water, DW).
Carbonicanhydrase, alkaline phospatase and malic dehydrogenase increased in
NaCl acclimationand H+- ATPase increased in KCl acclimation. It
did not have a transport correlate; it is not universal and differs among the
various amphibian species . In Bufoviridis,
higher NaCl acclimation caused a great decrease of MR cells' density, CA and a
dramaticdecreaseof both Iscand GCl. The high density
of mitochondria specifically in MR cells indicates high energy demands of the
activities in these cells, which could be related to the H+-
ATPase, and possibly other routes in these cells.
It was not possible to find concrete difference at the
EM level (X 12 000), betweenMR and other cells, following acclimation in NaCl
compared with NaNO3(100 mmol/l), whilst there is a great
difference in skin conductance (GCl) between these conditions. It is hard to
distinguish morphologically between the skin epithelium undergoing various acclimations
and treatments. Yet, the apical interdigitated folding could be more developed
conditions. There seems to be a larger space between the RCL and str. corneumin
the Cl- free
acclimated skins. On the whole, shape and state of cells look quietcomparable.
1.3. MR Cell Density and Regional Distribution over the Body
Density of Mitochondria-Rich Cells (DMRC) was
associated with Cl-conductance reversibly in a number of
species [6,30] under various conditions. This is
illustrated in Figure 1 that shows the
relationship of Dmrcand
in the skin of Bufoviridis. High environmental chloride brought to a substantial
decrease in MR cells density, except for KCl, acclimation. In the latter
as high as before or even increased (13, in frogs; 20, in toads), which was
attributed to blood acidification. A clue to the mechanism of this ontogenetic
adaptation may come from the work of Al-Awqati  in
the mammalian col- lecting duct, where the protein Hensin is involved in the
transformation of β to α
type of intercalated cells upon acidosis. The universality of this mechanism
remains to be found out .
The density of mitochondria-rich cells varies over the
body surface and among species. This was studied in anurans, revealing a
spatial distribution among species, characterized by a dorsoventral unevenness
that is more pronounced in the terrestrial species [15,31,33].
At the extreme we find the terrestrial Hylasp,
where no MR cells are found on the back side, while more or less even
distribution of MR cells over the whole body surface is found in the fossorial Pelobatessyriacusand
the semi-aquatic Xenopus
laevis [15,31,33]. It was suggested that the specific
unevenness dorso-ventral distribution of the MR cells is related to defense
against excessive evaporation, most pronounced in species that are greatly
exposed to air, i.e., Hylasp. Furthermore, examination of skin pieces
from opposite sides of Hylaarboreas howed that only the abdominal piece
that contains MR cells responded on the application of theophylline, a
phosphodiesterase inhibitor, while the back side skin that lacks MR cells was
neutral to the addition of the drug . The
later proofs explicitly the associations between MR cells and GCl .
1.4. Transport Functions
The two major epithelial cells' types, i.e. Pr and MR
cells, are set apart from each other and carry out singular functions
separately. The mechanism of sodium transport across frog skin was modeled and
has been firmly established, culminating in the now classical two membranes
model with general acclaim to all epithelia.
Unilateral chloride transport was localized to the mitochondria-rich cells, but
the mechanisms have not been established. Technically, this route is confined
to singly dispersed cells that are hard to be punctured continually and hard to
follow separately on either of their sides. They were studied directly usingexternal electric probe in totowhile Na+transport
is eliminated completely, either by replacement of apical Na+or
by the application of the specific inhibitor amiloride. Selective Cl-con-
ductance is thus localized exclusively to MR cells [10,35].
was demonstrated in the MR cells , but
several attempts to verification of H+secretion from these cells, did
not succeed[2,36]. These cells also contain
carbonic anhydrase [29,37]which is involved in
across the skin. Cell density, CA content
and both Iscand
ance dropped dramatically upon long term acclimation in higher NaCl. However, Katz and Gabbay,
 have demonstrated immunohistochemically, that the presence of
various components in these cells is not universal among species, and could not
be correlated with the measured transport properties of the epithelium. Any
interrelation between the two pathways has not been settled . The two cells' compartments respond
independently on the applica- tion of stimulators (hormons and agonists) and
inhibitors (such as amiloride). This is illustrated in Figure
2, where amiloride inhibits the short circuit current (Na+transport,
has only a negligible effect on the conductance. Theophylline, in the presence
of amiloride, ele- vated the conductance, which enhances Cl-transport.
In the absence of amiloride, addition of theophyline enhances both the current
Studies on skin transport of Xenopus laevisrepresent a particular
and opposite case [32,33,15]. This African
species lives mostly in water sources, it accumulates urea when accli- mated to
hypertonic solutions (22 and others), has a poor Na+ transport
capacity and no finite anion (Cl-) conductance. MR cells on the other
hand, are contained in the skin epithelium;they distribute equally over the
body surface and are comparable to other species. Yet, the density of these cells
decreased upon acclimation to high NaCl solutions .
The aligned functions in this and other species all containing MR cells remain
to be resolved.
Skin MR cells carry out particular transport functions
including Cl-, H+, HCO3-,
and organ- ic acid, except for Na+. Amiloride had no effect on electrolyte
concentrations in frog skin MR cells ;
however, a low level of basolateral Na+/K+ATPase
was discovered in intercalated cells of mouse kidney,
functioning apparently at housekeeping of the cells. Inamphibianskin epithelium
passive Cl-conductance is thus the primary species transported through MR
Figure 3 shows the
electrical properties of toad skin in open circuit condition. The effectsof
oxytocin, theophylline and the presence of external Cl-across the skin are
recorded. Itshows that in the absence of chloride, serosal oxytocin
hyperpolarizes greatly the skin electrical potential. Addition of theophyline
hardly had any effect, but upon replacement of chloride the potential is
depolarized greatly andimmediately.
1.5. Regulations - Hormonal and External Agents
Both Na+and Cl-pathways
in the skin are greatly affected by environmental salinity andare regulated
hormonally in diverse ways. The effect of cyclic AMP on Cl-conductance
in the skin epithelium was studied by Willumsen et al.
Katz and Nagel,  and others strengthen the
notion that Cl-pathway should contain two components: an
anion passive path which is regulated by a unilateral voltage
Adrenergic receptors turned to be effective on the
chloride pathway. Thus, activation of β-
adrenoceptors applied from the basolateral side increased GCl, which must
due to elevated cel- lular cAMP. Epinephrine antagonized this effect, and
exerted effective inhibition by the α1-
adrenoceptor also applied from the serosal side .
The effect of epinephrine did not overcome cAMP induced GCl, suggesting
it affects the regulatory component of the pathway. A distinct difference was
observed between direct application of cAMP and the use of agentsthought to
elevate cellular cAMP. Theophylline and forskolin which are supposed to elevate
cellular cAMP facilitated a great increase in GCl. However, the time dependent
increase of voltage conductance was eliminated upon direct application of cAMP
[the non hydrolysable analogues dibutyryl and 8-(4-Chlorophenylthio) cAMP], and
had somewhat stronger effect [35,40]. Mucosal
Application of N-ethylmaleimide (NEM) potently inhibited the chloride channel . Trypsin from the serosal side inhibited GClreversibly
by some 40%, which isdue to its effect on the regulatory component of the pathway.
1.6. Ontogenetic Development
Structural and physiological features of development
were investigated in two species, an anuran (Pelobates, [14,15]
and urodele (Salamander,. In both species
primordial cells were identified in the early developmental stages, while
mature, characteristic MR cells were revealed in the adult forms. Na+transport
and Cl-conductance emerge at maturity, and theyare cellularly
autonomous and morphologically separate from one another. Na+transport
measured as amiloride sensitive ISCoccurred in both species associated with
electricaltightening of the epithelium. However, even that at metamorphosis MR cells
appeared in both Cl-conductance was evident only in Pelobates,
and not in Salamander. It indicates that even
though MR cells are a specific route for Cl-, they may
fulfill other functions unrelated to that of Cl-transport, a
question that remains to be answered.
Graphic presentation is inherently limited. It helps
conceiving the cellular situation and used to test for alternatives, but is
limited for the actual and unknown functional roles played by these cells. It
rests on experimental evidence, and yet a passion for completeness. Models
should therefore be taken cautiously before recognized for reality. The two
membranes model is a good example case where a minimal graphic model manifested
itself as a general one applicable to all known epithelia. This has been used
ever since in numerous examples of epithelial transport in many animals and for
numerous specific tissues and solutes. Skin MR cell isanother example, where
the two membrane model was implicated. Here the models are based on those of
intercalated kidney tubules, i.e., α and β cells type, footing for H+or
secretion, while in the skin they are a major pathway for chloride conductance
and proton secre- tion. This led to a proposal of another γtype model for MR cell in amphibian
skin epithelium Figure 4. This model adds up
our present and more knowledge on the activities of this cell, but its reality
In conclusion, mitochondria rich cells in the skin
epithelium of amphibians are individually separated and are commonly present in
all species that were tested. They are silverstained, and are particularly rich
with mitochondria and carbonic anhydrase. Some othercharacteristics are also
noted, such as apical band 3 identified immune histochemicaly. These cells are
the major site of unilateral chloride conductance and H+secretion,
but despite their com- mon presence, these functions are not frequent in all species.
The emergence of MRcells, jointly
withfunctional Na+transportand Cl-conductancewere
followed in two species during ontogenesis. MR cells occurred in both species,
but Cl-conductance appeared only in the skin of Pelobates, not in that of the Urodele, Salmander. Amiloride sensitive Na+transport
assigned to principal cells occurred in both.[44-52]
Based on the use of specific inhibitors and stimulators, a simple model
composed of a passive anion pathway controlled by a regulatory component
governed through cAMP is proposed for the chloride conductance. Other functions
of these cells in all species are not re- solved.
Figure 1: Relationship of MR density and Cl- conductance across
the skin of Bufoviridis.
The upper panel shows there is no relation in control skins and the lower one
shows the relationship following voltage activation at 80 mV. NaCl ringer on
both sides. N=number of animals used. n=number of skin pieces used.
Figure 2: A short circuited toad skin (Bufoviridis) responding to amiloride
and theophyl- line. Application of amiloride blocked Na+ transport; addition of
theophylline enhanced (more than doubled), the skin conductance with no effect
on the current. Removal of amiloride reversed the current and improved the
conductance, while theophylline had a combined effect in the absence of
amiloride. Bars are the response to intermittent 3 mV voltage pulses. The skin
was bathed with NaCl on both sides.
Figure 3: Effects of oxytocin and theophylline on open circuit
transepithelial potential of a skin from Bufoviridis in the absence (NO3-) and presence of extracellular chloride. At
first, oxytocin was added in Cl- free external solution, leading to a large
increase in the transepithelial potential. Application of theophylline did not
have further effect. However, replacing the external solution with Cl- led to
prompt relax of the potential and decreased conductance.
Figure 4: Graphic presentation of functional epithelial cells.
Alpha and betha types play a role in H+
and HCO3- transport in various
epithelia; the gamma type depicts a possible situation in amphibians' skin
epithelium, and includes a number of transporters and channels in the same cell
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