© 2001 American Heart Association, Inc.
Editorials |
Mitochondria
Gateway for Cytoprotection
From the Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minn.
Correspondence to Andre Terzic, Guggenheim 7, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail terzic.andre{at}mayo.edu
Key Words: cardioprotection • energetics • metabolic signaling • potassium channel openers • heart
Tissues with high-energy turnover, such as heart muscle, heavily depend on ATP produced by mitochondrial oxidative phosphorylation, and therefore display particular vulnerability to insults induced by deprivation of oxygen and/or metabolic substrates.1,2 Along with oxidative phosphorylation, mitochondria are central in regulating Ca2+ signaling, free radical production, and release of apoptosis-inducing factors.3–7 Through dynamic feedback communication, mitochondrial functions are tightly integrated with cellular processes securing ionic and energetic homeostasis.2,8 In particular, phosphotransfer relays have emerged as mechanisms responsible for efficient coupling of mitochondrial ATP production with cellular sites of ATP utilization and/or ATP sensing.9–12 In this way, mitochondria can orchestrate vital processes throughout the cell, ultimately supporting cellular life and determining cell longevity.4,6,13 In fact, mitochondrial dysfunction disrupts cellular energy metabolism precipitating progression of degenerative disease states.13,14 Thus, preservation of mitochondria and associated energetic pathways has paramount significance in the ability of cardiomyocytes to withstand metabolic injury. Yet, little is known about mechanisms that would enhance mitochondrial tolerance to stress and induce cellular protection.
Recently, it has become apparent that mitochondria harbor sufficient functional plasticity to respond to metabolic challenge.15 By virtue of their ability to generate and accommodate stress-induced signals, mitochondria could serve as triggers and/or end-effectors in the cycle of events protecting mitochondrial integrity, transfer, and utilization of ATP and ultimately cell survival.2,7,13–17 Such new developments in our understanding of mitochondrial biology provide an exciting opportunity in enhancing cellular tolerance to stress by exploiting mitochondria-mediated cytoprotection.17
Several strategies that directly modulate mitochondrial respiration, ATP production, ion transport, cytochrome c release, redox state, and/or free radical generation have already been considered in cellular protection.17–20 Paradoxically, the majority of such approaches appear to confer protection after short-term perturbation of mitochondrial homeostasis initiating cytoprotective signaling events and priming the entry of mitochondria into a stress-resistant state. In particular, potassium channel opening drugs that preferentially target mitochondrial functions have emerged as powerful cardioprotective agents.20–29 Prototype drugs, such as diazoxide and nicorandil, reduce infarct size, salvage the myocardium, and enhance survival of cardiomyocytes under ischemic and/or hypoxic conditions.21–29 A direct effect of potassium channel openers on mitochondrial metabolism appears essential in preserving heart function against injury.28,30–32 In this regard, potassium channel openers mimic the effects of endogenous defense mechanisms induced by "conditioning" cycles comprising the preconditioning phenomenon.21–27 Preconditioning remodels cellular energy transduction, transfer, and utilization processes, engaging the myocardium into a state resistant to ischemia-reperfusion injury.33 However, the precise mechanisms responsible for preservation of cellular energetic systems still remain poorly understood.
In this issue of Circulation Research, Minners et al34 provide new evidence supporting the concept that moderate mitochondrial stress promotes cytoprotection. Ischemic preconditioning or preconditioning induced by pharmacological agents, such as potassium channel openers, promoted a cell survival program through modest mitochondrial uncoupling.34 In principle, reduction in mitochondrial membrane potential34 could alter mitochondrial redox state and reduce the generation of reactive oxygen species (ROS), thereby limiting oxidative damage.35,36 It is known that the high mitochondrial membrane potential, generated by the respiratory chain, suppresses electron transfer.35,36 This inhibits the coenzyme Q cycle, preventing oxidation of the semiquinone by reduced cytochrome b1, a downstream component in the respiratory chain.36 Consequently, the semiquinone becomes a long-lived radical (CoQH
) that could combine with molecular oxygen to produce ROS.36,37 In fact, hyperpolarization of the mitochondrial inner membrane has been demonstrated to precede excessive generation of ROS and the initiation of apoptotic events.38 Conversely, reduction of membrane potential with low concentrations of uncouplers or by direct inhibition of succinate dehydrogenase with malonate markedly reduces mitochondrial ROS generation.35,36 Moreover, a decrease in mitochondrial membrane potential associated with blunted ROS production has been observed with preconditioning and after mitochondrial treatment with carvedilol, an agent used in the management of heart failure.37,39,40 Therefore, modulators of mitochondrial ROS production are actively being considered for enhanced protection against oxidant injury.7,18,20,37 Evidence has been obtained revealing the ability of potassium channel openers and modulators of the mitochondrial redox state to protect mitochondrial structural and functional integrity by suppressing free radical generation at reoxygenation.37,41 Alternatively, a burst in free radical–dependent signaling has been proposed as a trigger mechanism initiating cardioprotective processes after cell exposure to potassium channel openers and other preconditioning stimuli.29,42 This could be due to the ability of ROS to act in concert with nitric oxide, ultimately targeting the mitochondrial respiratory chain to produce a protective phenotype.43,44 In fact, inhibitors of nitric oxide synthase (NOS) reduce protection afforded by preconditioning, whereas conversely, free radical scavengers blunt NOS activation, nitric oxide generation, and induction of cardioprotective signaling.43,45,46 Thus, short-term metabolic stress has the propensity of switching mitochondria into a stress-tolerant state and altering the mitochondrial-cytosolic communication.
In this way, moderately compromised mitochondrial function would induce changes in cellular energetics and intracellular nucleotide ratios.34 Such alterations could propagate mitochondrial signals to metabolic sensors and enhance energy transduction through glycolysis or alternative energetic pathways.2,34 Stimulation of glycolytic phosphotransfer and reduction in free radical production have been recently successfully applied in the clinical setting through use of novel mitochondria-targeting agents, trimetazidine and ranolazine, capable of enhancing myocardial resistance to ischemia.47,48 The beneficial effect of shifting cellular metabolism to glycolysis may not be limited to a less oxygen-requiring generation of ATP, but may actually rely on the ability of glycolytic phosphotransfer to facilitate delivery of ATP to ATP-utilizing sites.2,9 Enhanced energy delivery through glycolytic and adenylate kinase systems has been recognized as an adaptive mechanism in support of compromised energetics.2,10 Deletion of genes encoding creatine kinase or adenylate kinase compromise the ability of muscle to sustain the energetic economy under metabolic stress.49–53 Conversely, preconditioning induces redistribution of phosphotransfer through creatine kinase, adenylate kinase, and glycolytic pathways,33 and promotes cytoprotective AMP-driven signaling cascades.11,54–56 In turn, phosphotransfer reactions regulate the behavior of metabolic sensors, including sarcolemmal ATP-sensitive K+ (KATP) channels, an alarm mechanism that sets membrane excitability in response to metabolic stress.9,11,12,57 Knockout of genes encoding the pore-forming subunit of KATP channels produces an aberrant electrical response to ischemic or hypoxic challenge,58,59 whereas overexpression of channel proteins has been associated with enhanced cytoprotection.60,61 Targeting the mitochondrial respiratory chain would thus preserve not only mitochondrial functions but also the cellular energetic system as a whole. This is essential since accumulation of defects at various components of the cardiac energetic infrastructure, along with compromised compensatory mechanisms, precipitates myocardial dysfunction.2,62 In this regard, mitochondria have emerged as gateways responsible for launching and coordinating cellular protective programs and as targets for successful pharmacotherapy.21–30,34,63–66
Acknowledgments
Work in the authors’ laboratory is supported by the National Institutes of Health (HL64822), American Heart Association, Miami Heart Research Institute, Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery, and Marriott Foundation. P.P.D. and E.L.H. are recipients of Grants-in-Aid from the American Heart Association. C.O. holds a Fellowship from the American Heart Association. A.J. is a recipient of the CR75 Research Grant Award from the Mayo Foundation and the Merck Basic Science Award from the Society of Geriatric Cardiology. A.T. is an Established Investigator of the American Heart Association.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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