Download Not just the powerhouse of the cell: emerging

EDITORIAL
Cardiovascular Research (2010) 88, 5–6
doi:10.1093/cvr/cvq259
Not just the powerhouse of the cell: emerging roles
for mitochondria in the heart
Derek J. Hausenloy 1* and Marisol Ruiz-Meana 2
1
The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK; and 2Institut de Recerca, Hospital Vall d’Hebron, Universitat Autònoma de
Barcelona, Spain
Online publish-ahead-of-print 4 August 2010
This editorial refers to the following articles in this issue
which are part of the Review Focus on Mitochondria in
Cardiac Disease: Emerging Concepts and Novel Therapeutic
Targets: T. Miura et al.3, pp. 7 –15; D. Hausenloy et al.4,
pp. 67 –74; S.-B. Ong and D. Hausenloy6, pp. 16 –29; M. RuizMeana et al.7, pp. 30 –39; S.L. Hänninen et al.8, pp. 75 –82;
M.G. Rosca and C.L. Hoppel10, pp. 40 –50; C.-H. Chen
et al.13, pp. 51 –57; S.M. Davidson14, pp. 58 –66. It also refers
to the following articles in the next issue (Vol. 88, Issue 2):
M. Gucek and E. Murphy2; S. Cadenas et al.5; H. Bugger and
E.D. Abel9; D.A. Brown and B. O’Rourke11; V.B. Pillai et al.12
Mitochondria make up 30% of the volume of a single cardiomyocyte,
underlining the importance of their conventional role as the ATPproducing ‘powerhouse’ of the cell. However, it is clear that this
complex organelle plays a variety of roles within the cardiomyocyte
that extend beyond its established function as the cellular powerhouse. In this regard, the most significant discovery was its critical
role as an arbitrator of cell death1 in addition to its function in cellular
survival. This review focus highlights several novel and emerging roles
for mitochondria in the heart that may provide an opportunity for the
identification and development and of new therapeutic strategies for
the treatment of cardiac disease.
Several of the reviews contained in this spotlight issue explore the
role of mitochondria as targets for cardioprotection, i.e. protecting
the heart against the detrimental effects of acute ischaemia–reperfusion
injury (IRI). It is well established that mitochondrial dysfunction lies at
the heart of cardiomyocyte death induced by IRI. However, recent
evidence indicates that the contribution of mitochondria to cell
injury goes well beyond their role as death executors through the
opening of mitochondrial permeability transition pore (mPTP), as
they contain several specific and highly regulated intrinsic signalling
pathways and molecular complexes that may be determinants for
cell death or survival under stressful conditions. Several novel strategies for preserving mitochondrial function during acute IRI are
explored in this issue. To begin with, changes in mitochondrial
proteins (in terms of expression and post-translational modification,
termed the mitochondrial ‘proteome’) may provide valuable information in a variety of cardiac diseases. In this regard, Gucek and
Murphy2 review the changes in the mitochondrial proteome which
occur in a cardioprotective phenotype as a strategy for identifying
novel mediators of cardioprotection.
The convergence of a diverse variety of signal transduction
pathways originating from the cell surface to the mitochondria
has been reported to underlie the endogenous cardioprotective
phenomena of ischaemic preconditioning (IPC) and postconditioning. However, the actual signalling pathway linking the
cytosol to the mitochondrial matrix has eluded investigators. In
this respect, Miura et al. 3 review the current evidence supporting
a role for pro-survival protein kinase signalling to the mitochondria
in the context of myocardial protection. Whether these protein
kinases are able to interact directly with components of the mitochondria such as the mPTP, a critical determinant of IRI, or
whether they can influence mitochondrial function indirectly has
attracted vigorous debate. The paradoxical role of the mPTP as a
potential mediator of IPC is suggested in an original article by Hausenloy et al. 4 who have demonstrated that reactive oxygen species
(ROS)-induced activation of the pro-survival kinase Akt requires
the presence of the cyclophilin-D component of the mPTP. The
authors propose that non-pathological opening of the mPTP in
response to the IPC stimulus may be required prior to the index
ischaemic event to mediate IPC cardioprotection. In the context
of adaptation to myocardial ischaemia, evidence on the role of
hypoxia-inducible factor as a potential mediator of mitochondrial
metabolic reprogramming is provided and discussed in the review
by Cadenas et al.5
Mitochondrial morphology is a topic that has only very recently
been investigated in the heart. Mitochondria are dynamic organelles
that are able to undergo changes in morphology, generating either
elongated, interconnected networks by the process of mitochondrial
fusion or forming discrete, fragmented mitochondria by the process
of mitochondrial fission. Whether these phenomena are relevant to
the adult heart in which interfibrillar cardiac mitochondria have a
unique arrangement is discussed in a contribution by Ong and
Hausenloy.6 Specifically, these authors explore the potential for
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: +44 207 380 9888; fax: +44 207 388 5095, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected].
6
modulating mitochondrial morphology as a novel strategy for protecting against acute IRI, thereby providing new therapeutic targets for
cardioprotection.
Loss of calcium homeostasis is one of the main determinants of cardiomyocyte hypercontracture and cell death during reperfusion injury.
Interestingly, its role in cell death is not circumscribed to pathological
hyperactivation of contractile machinery but also involves induction of
mPTP opening in high-calcium microanatomical domains. Functional
units between mitochondria and sarcoplasmic reticulum (SR)
provide the basis for an efficient energy-demand coupling between
SR and mitochondria but they may trigger pathological mPTP
opening under conditions in which calcium and ROS production are
pathologically dysregulated. The consequences of the interaction
between SR and mitochondria in the setting of myocardial reperfusion
and other cardiovascular pathologies are highlighted in the review by
Ruiz-Meana et al.7 The tight molecular regulation of this interplay is
also exemplified in the original article by Hänninen et al. 8
who report that mitochondrial uncoupling results in a reduction in
SR calcium through down-regulation of the SR calcium buffer
calsequestrin (CASQ2).
Defects in mitochondrial bioenergetics are believed to underlie the
cardiac dysfunction in both diabetic patients and patients with cardiac
failure, topics that are reviewed by Bugger and Abel9 and Rosca and
Hoppel,10 respectively. The molecular mechanisms underlying this
mitochondrial dysfunction are described in detail for both diabetic
animal models and diabetic patients. Remarkably, efficient mitochondrial oxidative phosphorylation does not exclusively rely on the activities of individual electron transport chain complexes but also on their
appropriate supramolecular assembly into functional units or respirasomes. Insufficient respirasome formation, as well as changes in mitochondrial biogenesis and morphology and mitochondrial metabolic
remodelling that follows the development of cardiac failure, may
play an important pathophysiological role in failing myocardium.10
Several novel functions for cardiac mitochondria are introduced by
three other reviews. To begin with, an intriguing, new role for cardiac
mitochondria is in modulating the origin and propagation of arrhythmias within the heart. Brown and O’Rourke11 review the current evidence that implicates a number of mitochondrial ion channels as well
as oxidative stress in the generation of cardiac arrhythmias. These
findings raise the possibility of identifying a mitochondria-targeted
anti-arrhythmic therapy for preventing electrical dysfunction in the
heart.
‘Everyone wants to live forever’—and the answer may lie in cardiac
mitochondria. A potential role for cardiac mitochondria as purveyors
of cellular longevity is explored by Gupta and colleagues12 who
review the sirtuin family of histone deacetylases. The posttranslational effects of these enzymes have been implicated in
metabolism, cell growth, apoptosis, and the genetic control of
ageing. Sirtuins 3, 4, and 5 are present in cardiac mitochondria, and
the authors discuss that mitochondrial sirtuin 3 may confer protection
Editorial
against cardiac hypertrophy and oxidative stress. Mitochondria are the
major cellular source of ROS, but they may also play a decisive detoxifying role in protecting against oxidative stress. In this context, elimination of toxic aldehydes generated during a number of physiological
processes—such as lipid and carbohydrate metabolism—by the intramitochondrial aldehyde dehydrogenase-2 may represent an intrinsic
protective mechanism with great therapeutic potential for treating
acute IRI, as reviewed in detail by Mochly-Rosen and colleagues.13
Finally, Davidson14 summarizes the most important evidence supporting a role for endothelial mitochondria in the setting of cardiac
disease. Accordingly, mitochondrial calcium, oxidative stress, and
nitric oxide within endothelial cells have the potential to impact on
the development and progression of cardiac disease, highlighting the
importance of the endothelium as a potential therapeutic target for
the treatment of cardiac disease.
Therefore, the field of cardiac mitochondrial biology continues to
impress with the variety of emerging novel concepts highlighted in
this spotlight issue. We await with great anticipation the exciting
developments in this field of research which should result in the
identification of novel mitochondria-targeted therapeutic strategies
for treating cardiac disease.
Conflict of interest: none declared.
References
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