ReviewIschemic preconditioning: The role of mitochondria and aging
Highlights
► Mitochondria contribute to healthy aging. ► Mitochondria are central to ischemic cell damage and death. ► Ischemic preconditioning (IPC) acts via mitochondria to reduce damage. ► The efficacy of IPC diminishes in aged individuals. ► Understanding the mitochondria-IPC-aging axis may help to combat this problem.
Introduction
Stoppage of blood flow through the coronary arteries results in an acute lack of oxygen and deprives cardiomyocytes of substrates. When coupled with the restoration of blood flow, this results in ischemia–reperfusion (IR) injury. The subsequent development of myocardial infarction (MI) is a major cause of death, and the annual incidence of first-time MI in the US is 610,000. There are multiple risk factors for MI, but by far the greatest risk is age (Lloyd-Jones et al., 2010). Despite an increased focus on “heart health” in recent years, and a number of interventions that may reduce the risk of MI, there are few if any therapeutic avenues that reduce damage to the heart following an MI. Furthermore, co-morbidities such as obesity, type II diabetes, and aging ensure that MI is likely to remain a major clinical problem globally.
In 1986 it was discovered that “preconditioning” the heart with short periods of ischemia could alleviate damage incurred by a subsequent prolonged ischemic insult (Murry et al., 1986). It is also known that the prognosis following an MI is better for patients with unstable angina than those suffering an unpredicted MI (Ottani et al., 1995). These fundamental observations suggest that endogenous mechanisms exist in the heart to protect against future ischemic events. Many studies have attempted to define the signaling pathways induced by ischemic preconditioning (IPC) with the goal of developing pharmacologic mimics to provide protection (e.g. reduced infarct size, recovery of contractile function). The central problem has been that IPC itself is not effective in the aged heart (Fig. 1) (Boengler et al., 2009a, Jahangir et al., 2007, Bartling et al., 2003).
Aging is associated with an accumulation of pathologic changes leading to a progressive decline in cellular, organ and whole organism function. In addition, aging results in a lower resistance to stress (Shih and Yen, 2007). Mitochondria have been recognized to play a prominent role in aging, and a decline in mitochondrial function is thought to underlie some of the decline in tissue function with age. In addition, the mitochondrial signaling pathways leading to cell injury and death may be disrupted during aging.
Counteracting the role of mitochondria in pathology however, is the fact that they are known to be critically involved in the protection afforded by IPC. Thus developing a clear understanding of how aging influences the mitochondrial balance between ischemic damage and protection is essential to devise effective therapeutic strategies for cardioprotection in older adults.
Section snippets
Cardiac mitochondria: basic function, and role in IR injury
Cardiac contractile function relies on mitochondrial oxidative phosphorylation (Ox-Phos) for the bulk of its ATP. While mitochondria are the metabolic hub of all eukaryotic cells, mitochondria from different organs are adapted to specific functions (Johnson et al., 2007). Specifically, cardiac mitochondria are known to preferentially oxidize fatty acids (Stanley et al., 2005). Moreover, cardiac mitochondria exist in two subpopulations: subsarcolemmal (SSM) and interfibrillar mitochondria (IFM),
Cardiac mitochondria and IR injury: the effects of aging
As shown in Fig. 1, the aging heart is more sensitive to IR injury (Lesnefsky et al., 2006, Lesnefsky et al., 2001b). In addition, a significant decline in cardiac mitochondrial function is seen in aging, and this appears to differ between IFM and SSM (Judge et al., 2005, Fannin et al., 1999). This section will focus on two mitochondrial commonalties between aging and IR injury: (i) mitochondrial Ca2 + handling and (ii) mitochondrial ROS generation/oxidative damage.
The Ca2 + insult associated
Ischemic preconditioning, aging and mitochondria
One strategy to protect the heart from IR injury is IPC (Murry et al., 1986), which can be used clinically in transplant and coronary surgeries (Ji et al., 2007). Similar to IPC, protection can also be achieved via ischemic postconditioning during reperfusion (Zhao et al., 2003). This is a process whereby short periods of ischemia are applied following the index ischemic insult. Like IPC, the effectiveness of postconditioning also decreases with age (Boengler et al., 2008), though whether these
Current research
Despite numerous IPC mimicking drugs discovered in the laboratory, none has yet made the transition to clinical use, with the result that there are currently no FDA approved drugs for the indication of reducing myocardial infarct size. One reason for this may be that most MI patients are neither young nor healthy, whereas pharmacologic agents are often developed in the laboratory using young animals (Hausenloy et al., 2010, Downey and Cohen, 2009). Examples of normally-efficacious agents which
Conclusions
Multiple signaling pathways interface at the mitochondrion to influence longevity and IPC. Elucidating the mechanisms of loss of IPC efficacy in aging remains a major problem in cardiovascular research, which demands the development of novel treatment strategies for myocardial infarction in aged individuals. Mitochondria both contribute to the pathology of IR injury and are critical mediators of cardioprotective signaling. Current research focusing on lifestyle interventions such as caloric
Acknowledgments
Funding was provided by US National Institutes of Health grants RO1-HL071158 (to PSB) and RO1-GM-087483 (to PSB and KN) and an American Heart Association, Founder Affiliate Postdoctoral Fellowship Award 11POST7290028 (to APW).
References (114)
- et al.
Ischemic preconditioning in the aging heart: from bench to bedside
Ageing Res. Rev.
(2010) - et al.
Ischemic preconditioning is not cardioprotective in senescent human myocardium
Ann. Thorac. Surg.
(2003) - et al.
Cardioprotection by metabolic shut-down and gradual wake-up
J. Mol. Cell. Cardiol.
(2009) - et al.
The cardioprotective effects elicited by p66(Shc) ablation demonstrate the crucial role of mitochondrial ROS formation in ischemia/reperfusion injury
Biochim. Biophys. Acta
(2009) - et al.
Age-related increases in oxidatively damaged proteins of mouse kidney mitochondrial electron transport chain complexes
Free Radic. Biol. Med.
(2007) - et al.
Hypoxic preconditioning requires the apoptosis protein CED-4 in C. elegans
Curr. Biol.
(2007) - et al.
The cell-non-autonomous nature of electron transport chain-mediated longevity
Cell
(2011) - et al.
Tissue protection mediated by mitochondrial K + channels
Biochim. Biophys. Acta
(2006) - et al.
Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria
Arch. Biochem. Biophys.
(1999) - et al.
Cardioprotective signaling to mitochondria
J. Mol. Cell. Cardiol.
(2009)
K(ATP) channels and preconditioning: a re-examination of the role of mitochondrial K(ATP) channels and an overview of alternative mechanisms
J. Mol. Cell. Cardiol.
Bioenergetics and permeability transition pore opening in heart subsarcolemmal and interfibrillar mitochondria: effects of aging and lifelong calorie restriction
Mech. Ageing Dev.
Increased calcium vulnerability of senescent cardiac mitochondria: protective role for a mitochondrial potassium channel opener
Mech. Ageing Dev.
Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine
Free Radic. Biol. Med.
The cardioprotective effect of uridine and uridine-5′-monophosphate: the role of the mitochondrial ATP-dependent potassium channel
Exp. Gerontol.
Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse
Arch. Biochem. Biophys.
Mitochondrial calcium and the permeability transition in cell death
Biochim. Biophys. Acta
Ischemic injury to mitochondrial electron transport in the aging heart: damage to the iron–sulfur protein subunit of electron transport complex III
Arch. Biochem. Biophys.
Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure
J. Mol. Cell. Cardiol.
Aging defect at the QO site of complex III augments oxyradical production in rat heart interfibrillar mitochondria
Arch. Biochem. Biophys.
Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle
J. Biol. Chem.
p66(shc) is highly expressed in fibroblasts from centenarians
Mech. Ageing Dev.
Reactive oxygen species generated from the mitochondrial electron transport chain induce cytochrome c dissociation from beef-heart submitochondrial particles via cardiolipin peroxidation. Possible role in the apoptosis
FEBS Lett.
Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation
Cell Metab.
Redox regulation of the mitochondrial K(ATP) channel in cardioprotection
Biochim. Biophys. Acta
Extending life span by increasing oxidative stress
Free Radic. Biol. Med.
How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis)
Exp. Gerontol.
Differential age-related changes of MAO-A and MAO-B in mouse brain and peripheral organs
Neurobiol. Aging
Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
J. Mol. Biol.
Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans
J. Biol. Chem.
Preconditioning, anesthetics, and perioperative medication
Best Pract. Res. Clin. Anaesthesiol.
Survival from hypoxia in C. elegans by inactivation of aminoacyl-tRNA synthetases
Science
Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals
FASEB J.
Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43
Am. J. Physiol. Heart Circ. Physiol.
Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice
Circ. Res.
Loss of cardioprotection with ageing
Cardiovasc. Res.
Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria
Basic Res. Cardiol.
Age related changes in NAD + metabolism oxidative stress and Sirt1 activity in wistar rats
PLoS One
Calcium, ATP, and ROS: a mitochondrial love-hate triangle
Am. J. Physiol. Cell Physiol.
Long-lived mitochondrial (Mit) mutants of Caenorhabditis elegans utilize a novel metabolism
FASEB J.
HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans
PLoS Genet.
Rates of behavior and aging specified by mitochondrial function during development
Science
Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans
Genes Dev.
Redox signaling triggers protection during the reperfusion rather than the ischemic phase of preconditioning
Basic Res. Cardiol.
Why do we still not have cardioprotective drugs?
Circ. J.
Signaling pathways in ischemic preconditioning
Heart Fail. Rev.
Exercise training promotes SIRT1 activity in aged rats
Rejuvenation Res.
Superoxide radical: an endogenous toxicant
Annu. Rev. Pharmacol. Toxicol.
Pharmacological facilitation of primary percutaneous coronary intervention for acute myocardial infarction: is the slope of the curve the shape of the future?
JAMA
SIRT1 negatively regulates the mammalian target of rapamycin
PLoS One
Cited by (62)
Aging, sex and NLRP3 inflammasome in cardiac ischaemic disease
2022, Vascular PharmacologyMetformin and myocardial ischemia and reperfusion injury: Moving toward “prime time” human use?
2021, Translational ResearchTargeting ER stress and calpain activation to reverse age-dependent mitochondrial damage in the heart
2020, Mechanisms of Ageing and DevelopmentUse the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species
2018, Journal of Molecular BiologyCitation Excerpt :The IM has numerous K+ channels that allow K+ flux into the matrix when activated [109]. K+ channels are diversely regulated and widely implicated in many signaling paradigms [110–112]. Changes in K+ levels in mitochondria are implicated in the maintenance of mitochondrial matrix volume and modulation of mitochondrial function.
Metabolic Stress, Autophagy, and Cardiovascular Aging: from Pathophysiology to Therapeutics
2018, Trends in Endocrinology and MetabolismCitation Excerpt :In particular, AGEs abridge the free radical with the glycation theories in aging. The mitochondrial decline theory highlights declines in mitochondrial ATP supply manifested as loss of mitochondria and appearance of swollen and defective mitochondria in aging [30]. Telomere shortening governs senescence with defective telomeres serving as an indicator of cardiovascular aging [31,32].
Improved heart function from older donors using pharmacologic conditioning strategies
2016, Journal of Heart and Lung Transplantation