Targeting ER stress and calpain activation to reverse age-dependent mitochondrial damage in the heart
Introduction
Cardiac mitochondria are the primary source to meet the energy demand for a constantly beating heart (Lesnefsky et al., 2016). There are two distinct populations of cardiac mitochondria: subsarcolemmal mitochondria (SSM), which reside under the sarcolemma, and interfibrillar mitochondria (IFM), present between myofibrils (Palmer et al., 1985). Although SSM are more sensitive to ischemia-mediated mitochondrial damage (Lesnefsky et al., 1997), IFM are the population mainly affected in aged hearts (Fannin et al., 1999). Aging-induced mitochondrial defects lead to decreased ATP production and increased ROS generation that potentiate cardiac injury during ischemia-reperfusion (Lesnefsky et al., 2001a). Moreover, most cardiac protective strategies are relatively ineffective in aged hearts (Peart et al., 2014). This review focuses on the potential of novel approaches targeting ER stress and calpain activation to decrease age-related exacerbation of cardiac injury following ischemia-reperfusion.
Section snippets
ETC damage in aged hearts
A detailed description of aging-induced mitochondrial defects can be found in several excellent reviews (Lesnefsky et al., 2016, 2017; Lesnefsky et al., 2001c). In brief, the rate of oxidative phosphorylation is decreased in IFM isolated from 24 month old Fisher 344 rat hearts. In contrast, oxidative phosphorylation is not markedly altered in SSM from aged rat hearts (Fannin et al., 1999). Direct measurement of enzyme activities shows that aging leads to decreased activities of electron
Role of oxidative stress in mitochondrial damage during aging
Oxidative stress plays a key role in aging-induced mitochondrial dysfunction (Moghaddas et al., 2003). Over expression of mitochondria-targeted catalase protects aged hearts, supporting the idea that mitochondrial ROS generation contributes to the mitochondrial dysfunction observed in aged hearts (Bhuiyan and Fukunaga, 2009). The ETC is a key source of ROS generation in cardiac mitochondria (Chen et al., 2003). Decreased complex III activity contributes to increased ROS generation in aged IFM
Impairment of endogenous signal transduction in aged hearts
Aged hearts are more susceptible to cardiac injury during ischemia-reperfusion (D’ Annunzio et al., 2016; Lesnefsky et al., 1994, 1996). Classical cardio-protective approaches including ischemic pre/post-conditioning are not effective in aged hearts (D’ Annunzio et al., 2016; Wojtovich et al., 2012). Ischemic preconditioning (IPC) activates a number of protective signaling cascades that eventually converge at the mitochondria. The potential mechanisms underlying the loss of IPC protection in
Summary
The presence of dysfunctional mitochondria in aged hearts increases cardiac injury during ischemia-reperfusion. Targeting mitochondrial function in aged hearts by acute intervention at the onset of reperfusion can decrease cardiac injury during ischemia-reperfusion. Obviously, a better approach is to restore mitochondrial function in aged hearts before injury. This approach not only eliminates mitochondrial dysfunction-induced cell injury, but also may enable traditional therapeutic approaches
Declaration of Competing Interest
The authors state they have no conflict of interest or financial interests to disclose.
Acknowledgements
The critical review of this manuscript by Dr. Edward Lesnefsky (Pauley Heart Center, Virginia Commonwealth University and Medical Service, McGuire Veterans Affairs Medical Center) is greatly appreciated. This work was supported by R21 AG049461 (Q.C.) from the National Institute on Aging, the Department of Veterans Affairs Office of Research and Development, Medical Research Service Merit Review Award (2IO1BX001355-01A2) (QC, EJL), and a Pauley Heart Center Pilot Project from Virginia
References (126)
- et al.
Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart
Exp. Gerontol.
(2005) - et al.
The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response
J. Lipid Res.
(2009) - et al.
Cardioprotection with cariporide, a sodium-proton exchanger inhibitor, after prolonged ischemia and reperfusion in senescent rats
Exp. Gerontol.
(2004) - et al.
Mitochondrial dynamics: orchestrating the journey to advanced age
J. Mol. Cell. Cardiol.
(2015) - et al.
Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3
Cell Metab.
(2005) - et al.
Mitochondrial permeability transition: a molecular lesion with multiple drug targets
Trends Pharmacol. Sci.
(2019) - 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.
Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain
Free Radic. Biol. Med.
(2006) - et al.
Blockade of electron transport during ischemia preserves bcl-2 and inhibits opening of the mitochondrial permeability transition pore
FEBS Lett.
(2011) - et al.
Heart mitochondria and calpain 1: location, function, and targets
Biochim. Biophys. Acta
(2015)