EDITORIAL
Cardiovascular Research (2016) 110, 4–5
doi:10.1093/cvr/cvw041
Mitochondrial potassium homeostasis: a central
player in cardioprotection
Rainer Schulz 1* and Fabio Di Lisa 2
1
Institute of Physiology, Justus-Liebig University Giessen, Aulweg 129, Giessen 35392, Germany; and 2Department of Biomedical Sciences and CNR Institute of Neurosciences, University of
Padova, Padova, Italy
This editorial refers to ‘Expression and function of Kv7.4
channels in rat cardiac mitochondria: possible targets for
cardioprotection’ by L. Testai et al., pp. 40– 50.
Mitochondria play a central role in energy metabolism and ionic
homeostasis through which they are involved in the initiation of or prevention from cell death. In particular, mitochondrial derangements contribute to cardiac diseases by decreasing ATP, altering intracellular
Ca2+ homoeostasis and generating reactive oxygen species (ROS).1
Therefore, the maintenance of mitochondrial structure and function
is crucial for cardioprotection, as especially characterized in the context of ischaemia/reperfusion injury.
Mitochondria convert the energy released from the flow of electrons along the respiratory chain into the electrogenic proton pumping
across the inner mitochondrial membrane (IMM). The resulting electrochemical proton gradient or proton motive force (Dp) is the driving
force for any energy-utilizing process occurring within mitochondria,
including ATP synthesis. Both the electrical (Dc) and the chemical
(DpH) components of Dp are involved in movements of anions and cations across the IMM. In particular, the very high Dc (negative inside)
drives the uptake of cations through mitochondrial channels that are
nuclear encoded and imported via translocases located in the outer
mitochondrial membrane and IMM.2 Although, in cardiac pathophysiology, a major focus has been given to mitochondrial calcium (Ca2+)
homeostasis, an increasing attention is devoted to potassium (K+)
movements across the IMM.
The electrophoretic uptake of K+ into the mitochondrial matrix
occurs through both diffusive leak pathways and various channels.
The efflux pathway is represented by the K+/H+ exchanger (for
review, see ref. 3). Unfortunately, the molecular identification of these
transporters is still incomplete. Thus, the pathophysiological role of
mitochondrial K+ movements still lacks convincing demonstration
generated by genetic approaches.
In cardiovascular pathophysiology, major relevance has been attributed
to the big-conductance potassium channel controlled by calcium (BKCa),4
the adenosine triphophate (ATP)-dependent potassium channel (mtKATP),5
with the Renal Outer Medullary K+ (ROMK) channel reported as its pore
forming subunit,6 connexin 43,7 and the K+/H+ exchanger.8
Figure 1 illustrates channels and transporters in the IMM. K+ influx is
accompanied by osmotically obligated water, that is likely to be
mediated by aquaporins (AQP), resulting in matrix swelling.9 Due to
the high Dc, if unopposed mitochondrial K+ uptake would result
into massive swelling leading to mitochondrial fragmentation and cell
death.8 This adverse outcome is curtailed by the K+/H+ exchanger.
The resulting K+ cycle establishes a new steady state characterized
by a minor degree of matrix swelling and alkalinization, Dc decrease
and ROS formation. The drop in Dc reduces the driving force for
Ca2+ uptake, while the slight swelling appears to promote substrate
oxidation.6 Therefore, the mitochondrial K+ cycle appears to modulate
energy metabolism, redox reactions, and ionic homeostasis.
Under physiological conditions, open probability of K+ channels appears to be low, but forced opening of mitochondrial K+ channels prior
to a sustained lethal phase of myocardial ischaemia/reperfusion reduces
the extent of irreversible damage (‘pharmacological conditioning’). The
protective mechanism seems to integrate various beneficial actions,
such as ATP sparing, a reduced mitochondrial Ca2+ uptake that along
with a slight increase in ROS formation10,11 is likely to antagonize
reperfusion-induced opening of the mitochondrial permeability transition pore.6 However, it must be pointed out that the evidence of cardioprotection related to mtKATP has been obtained only by
pharmacological approaches using non-specific compounds. Thus,
the role of mtKATP in conditioning phenomena remains a controversial
issue.12 Challenging the notion that a moderate increase in ROS is a
relevant part of protection elicited by mtKATP opening, endothelial oxidative stress appears to be reduced by mtKATP inhibition.13 In addition,
a reduced mitochondrial K+ uptake induced by inhibition of Kv1.3
channels has been shown to promote lymphocyte apoptosis.3 Therefore, the relationship between opening of mitochondrial K+ channels,
ROS formation and cytoprotection is far from being clear.
Testai et al. 14 now demonstrate one more potassium channel normally expressed at the sarcolemma of cardiomyocytes (Kv7) to be present
also in mitochondria. In rat hearts, the authors identified Kv7.1 and Kv7.4
being expressed with Kv7.4 being located mainly in mitochondrial membranes (40% being positive for antibody staining). Opening of Kv7.4
channels using retigabine increased thallium (K+ analogue) influx into
isolated cardiac mitochondria, but not into liver mitochondria lacking expression of Kv7.4. Opening of Kv7.4 channels reduced cardiac mitochondrial membrane potential and Ca2+ influx but increased ROS formation,
all changes being prevented by co-treatment with the Kv7 channel inhibitor Xe991. While both retigabine and Xe991 had effect on viability of
H9C2 cells prior to anoxia/reoxygenation, retigabine increased cell
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
* Corresponding author. Tel: 06 41 99 4 72 40; fax: 06 41 99 4 72 39, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
5
Editorial
Figure 1 Major pathways for K+ movements across the inner mitochondrial membrane. IMS, inter-membrane space; IMM, inner mitochondrial membrane; Cx43, connexin 43; AQP, aquaporin; BKCa, big-conductance potassium channel; KATP, adenosine triphophate-dependent potassium channel;
ROMP, Renal Outer Medullary potassium (K+, ROMK) pore; H+, protons; ETC, electron transport chain; H2O, water; Dc, membrane potential:
Ca2+, calcium ions; PTP, permeability transition pore; ROS, reactive oxygen species.
survival following anoxia/reoxygenation. Finally, in isolated rat hearts, retigabine reduced infarct size and increased functional recovery following
ischaemia/reperfusion; these protective effects of retigabine seen in
H9C2 cells and isolated rat hearts were blocked by Xe991.
Clearly, some caveats must be given to the results in that the localization of Kv7.4 in mitochondria were based on antibody experiments using
confocal laser scan or electron microscopy combined with western blot
which always bare the risk of false positive results given to cross reactivity
of antibodies and/or contamination. Also the functional assessments are
based primarily on pharmacological agonist and antagonist approaches
with the possibility of non-selectivity of the used agents although the
authors tried the very best to rule out such unspecific effects using liver
mitochondria not containing Kv7.4 as negative controls.
What is the charm of the present results: within cardiomyocytes
Kv7.4 is mainly expressed in mitochondria potentially allowing for a selective cardioprotective strategy with little side effects such as arrhythmogenesis. However, Kv7.4 have been demonstrated to be expressed
in the vascular wall and to be important in the regulation of vascular
tone15; therefore, in vivo experiments and genetic approaches are required to prove whether Kv7.4 in cardiac mitochondria can be opened
to protect the heart against ischaemia/reperfusion injury without significant disturbances in vascular tone. It will be also worth clarifying
what is the link between Kv7.4 and the other mitochondrial K+ channels and investigating whether Kv7.4 opening is beneficial also against
maladaptive remodelling.
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